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Ambarki, Khalid
Publications (10 of 36) Show all publications
Zarrinkoob, L., Wåhlin, A., Ambarki, K., Birgander, R., Eklund, A. & Malm, J. (2019). Blood flow lateralization and collateral compensatory mechanisms in patients with carotid artery stenosis. Stroke, 50(5), 1081-1088
Open this publication in new window or tab >>Blood flow lateralization and collateral compensatory mechanisms in patients with carotid artery stenosis
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2019 (English)In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 50, no 5, p. 1081-1088Article in journal (Refereed) Published
Abstract [en]

Background and Purpose: Four-dimensional phase-contrast magnetic resonance imaging enables quantification of blood flow rate (BFR; mL/min) in multiple cerebral arteries simultaneously, making it a promising technique for hemodynamic investigation in patients with stroke. The aim of this study was to quantify the hemodynamic disturbance and the compensatory pattern of collateral flow in patients with symptomatic carotid stenosis.

Methods: Thirty-eight patients (mean, 72 years; 27 men) with symptomatic carotid stenosis (>/=50%) or occlusion were investigated using 4-dimensional phase-contrast magnetic resonance imaging. For each patient, BFR was measured in 19 arteries/locations. The ipsilateral side to the symptomatic carotid stenosis was compared with the contralateral side.

Results: Internal carotid artery BFR was lower on the ipsilateral side (134+/-87 versus 261+/-95 mL/min; P<0.001). BFR in anterior cerebral artery (A1 segment) was lower on ipsilateral side (35+/-58 versus 119+/-72 mL/min; P<0.001). Anterior cerebral artery territory bilaterally was primarily supplied by contralateral internal carotid artery. The ipsilateral internal carotid artery mainly supplied the ipsilateral middle cerebral artery (MCA) territory. MCA was also supplied by a reversed BFR found in the ophthalmic and the posterior communicating artery routes on the ipsilateral side (-5+/-28 versus 10+/-28 mL/min, P=0.001, and -2+/-12 versus 6+/-6 mL/min, P=0.03, respectively). Despite these compensations, BFR in MCA was lower on the ipsilateral side, and this laterality was more pronounced in patients with severe carotid stenosis (>/=70%). Although comparing ipsilateral MCA BFR between stenosis groups (<70% and >/=70%), there was no difference ( P=0.95).

Conclusions: With a novel approach using 4-dimensional phase-contrast magnetic resonance imaging, we could simultaneously quantify and rank the importance of collateral routes in patients with carotid stenosis. An important observation was that contralateral internal carotid artery mainly secured the bilateral anterior cerebral artery territory. Because of the collateral recruitment, compromised BFR in MCA is not necessarily related to the degree of carotid stenosis. These findings highlight the importance of simultaneous investigation of the hemodynamics of the entire cerebral arterial tree.

Place, publisher, year, edition, pages
Philadelphia: Lippincott Williams & Wilkins, 2019
Keywords
carotid stenosis, circle of Willis, humans, magnetic resonance imaging, cine, middle cerebral artery
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-158003 (URN)10.1161/STROKEAHA.119.024757 (DOI)000469350000029 ()30943887 (PubMedID)
Funder
Swedish Research Council, 2015-05616Swedish Research Council, 2017-04949Västerbotten County CouncilSwedish Heart Lung Foundation, 20140592
Available from: 2019-04-10 Created: 2019-04-10 Last updated: 2019-06-17Bibliographically approved
Kristiansen, M., Linden, C., Qvarlander, S., Wåhlin, A., Ambarki, K., Hallberg, P., . . . Jóhannesson, G. (2018). Blood flow rate of ophthalmic artery in patients with normal tension glaucoma and healthy controls. Paper presented at Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO), APR 29-MAY 03, 2018, Honolulu, HI. Investigative Ophthalmology and Visual Science, 59(9)
Open this publication in new window or tab >>Blood flow rate of ophthalmic artery in patients with normal tension glaucoma and healthy controls
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2018 (English)In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 59, no 9Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Purpose: To determine the blood flow rate of the ophthalmic artery (OA) in patients with Normal Tension Glaucoma (NTG) compared to age-matched healthy controls using phase-contrast magnetic resonance imaging (PCMRI).

Methods: Seventeen patients with treated NTG (11 female; mean age: 70±9 years) and 16 age-matched healthy controls (10 female; mean age: 71±9 years) underwent PCMRI using a 3-Tesla scanner as well as ophthalmological examinations including visual acuity, Goldmann Applanation Tonometry, Humphrey perimetry and fundoscopy. Ophthalmic blood flow was acquired using a 2D PCMRI sequence set to a spatial resolution of 0.35mm/pixel. Mean flow rate and cross-sectional area was calculated using Segment Software. The eye with the most severe glaucomatous damage classified by visual field index (VFI) was chosen for comparison. The primary outcome was blood flow rate of OA.

Results: The mean VFI was 41% ± 26 (mean±SD) for the worse NTG eyes. The intraocular pressure was 13.6±2.6 mmHg for NTG eyes and 13.8±2.1 mmHg for control eyes. The blood flow rate in the NTG group was 9.6±3.7 ml/min compared to 11.8±5.5 ml/min in the control group. The area was 1.7±0.3 mm2 and 2.0±0.6 mm2 respectively. No statistical significance was found between NTG and the control group regarding blood flow rate (p=0.07) or OA area (p=0.12).

Conclusions: Despite OA being an anastomosis between the intracranial and extracranial circulation, possibly generating an eye unrelated variability in blood flow, we found a trend level reduction of approximately 2 ml/min in NTG. The finding warrants blood flow rate analysis of smaller arteries specifically supplying the eye, e.g. the central retinal artery.

Place, publisher, year, edition, pages
The Association for Research in Vision and Ophthalmology, 2018
National Category
Ophthalmology
Identifiers
urn:nbn:se:umu:diva-152420 (URN)000442932805099 ()
Conference
Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO), APR 29-MAY 03, 2018, Honolulu, HI
Funder
Swedish Society for Medical Research (SSMF)The Swedish Medical Association
Available from: 2018-10-05 Created: 2018-10-05 Last updated: 2018-10-08Bibliographically approved
Dunås, T., Wåhlin, A., Ambarki, K., Zarrinkoob, L., Malm, J. & Eklund, A. (2017). A Stereotactic Probabilistic Atlas for the Major Cerebral Arteries. Neuroinformatics, 15(1), 101-110
Open this publication in new window or tab >>A Stereotactic Probabilistic Atlas for the Major Cerebral Arteries
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2017 (English)In: Neuroinformatics, ISSN 1539-2791, E-ISSN 1559-0089, Vol. 15, no 1, p. 101-110Article in journal (Refereed) Published
Abstract [en]

Improved whole brain angiographic and velocity-sensitive MRI is pushing the boundaries of noninvasively obtained cerebral vascular flow information. The complexity of the information contained in such datasets calls for automated algorithms and pipelines, thus reducing the need of manual analyses by trained radiologists. The objective of this work was to lay the foundation for such automated pipelining by constructing and evaluating a probabilistic atlas describing the shape and location of the major cerebral arteries. Specifically, we investigated how the implementation of a non-linear normalization into Montreal Neurological Institute (MNI) space improved the alignment of individual arterial branches. In a population-based cohort of 167 subjects, age 64-68 years, we performed 4D flow MRI with whole brain volumetric coverage, yielding both angiographic and anatomical data. For each subject, sixteen cerebral arteries were manually labeled to construct the atlas. Angiographic data were normalized to MNI space using both rigid-body and non-linear transformations obtained from anatomical images. The alignment of arterial branches was significantly improved by the non-linear normalization (p < 0.001). Validation of the atlas was based on its applicability in automatic arterial labeling. A leave-one-out validation scheme revealed a labeling accuracy of 96 %. Arterial labeling was also performed in a separate clinical sample (n = 10) with an accuracy of 92.5 %. In conclusion, using non-linear spatial normalization we constructed an artery-specific probabilistic atlas, useful for cerebral arterial labeling.

Keywords
Cerebral arteries, Probabilistic atlas, 4D flow MRI, Automatic labeling, Spatial normalization
National Category
Clinical Medicine
Identifiers
urn:nbn:se:umu:diva-131144 (URN)10.1007/s12021-016-9320-y (DOI)000394260000009 ()27873151 (PubMedID)2-s2.0-84996542654 (Scopus ID)
Available from: 2017-02-06 Created: 2017-02-06 Last updated: 2018-06-09Bibliographically approved
Edsbagge, M., Andreasson, U., Ambarki, K., Wikkelsø, C., Eklund, A., Blennow, K., . . . Tullberg, M. (2017). Alzheimer's Disease-Associated Cerebrospinal Fluid (CSF) Biomarkers do not Correlate with CSF Volumes or CSF Production Rate. Journal of Alzheimer's Disease, 58(3), 821-828
Open this publication in new window or tab >>Alzheimer's Disease-Associated Cerebrospinal Fluid (CSF) Biomarkers do not Correlate with CSF Volumes or CSF Production Rate
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2017 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 58, no 3, p. 821-828Article in journal (Refereed) Published
Abstract [en]

Background: Neuropathologically, Alzheimer's disease (AD) is characterized by accumulation of a 42 amino acid peptide called amyloid-beta (A beta(42)) in extracellular senile plaques together with intraneuronal inclusions of hyperphosphorylated tau protein in neurofibrillary tangles and neuronal degeneration. These changes are reflected in the cerebrospinal fluid (CSF), the volumes and production rates of which vary considerably between individuals, by reduced concentration of A beta(42), increased concentration of phosphorylated tau (P-tau) protein, and increased concentration of total tau (T-tau) protein, respectively. Objective: To examine the outstanding question if CSF concentrations of AD associated biomarkers are influenced by variations in CSF volumes, CSF production rate, and intracranial pressure in healthy individuals. Methods: CSF concentrations of A beta(42), P-tau, and T-tau, as well as a number of other AD-related CSF biomarkers were analyzed together with intracranial subarachnoid, ventricular, and spinal CSF volumes, as assessed by magnetic resonance imaging volumetric measurements, and CSF production rate in 19 cognitively normal healthy subjects (mean age 70.6, SD 3.6 years). Results: Negative correlations were seen between the concentrations of three CSF biomarkers (albumin ratio, A beta(38), and A beta(40)), and ventricular CSF volume, but apart from this finding, no significant correlations were observed. Conclusion: These results speak against inter-individual variations in CSF volume and production rate as important confounds in the AD biomarker research field.

Place, publisher, year, edition, pages
IOS Press, 2017
Keywords
Alzheimer's disease, amyloid-beta, biomarkers, cerebrospinal fluid, healthy subjects, production rate, tau protein, volume
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-137412 (URN)10.3233/JAD-161257 (DOI)000402995800019 ()28505972 (PubMedID)
Available from: 2017-07-04 Created: 2017-07-04 Last updated: 2018-06-09Bibliographically approved
Qvarlander, S., Ambarki, K., Wåhlin, A., Jacobsson, J., Birgander, R., Malm, J. & Eklund, A. (2017). Cerebrospinal fluid and blood flow patterns in idiopathic normal pressure hydrocephalus. Acta Neurologica Scandinavica, 135(5), 576-584
Open this publication in new window or tab >>Cerebrospinal fluid and blood flow patterns in idiopathic normal pressure hydrocephalus
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2017 (English)In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 135, no 5, p. 576-584Article in journal (Refereed) Published
Abstract [en]

Objectives: Increased aqueduct cerebrospinal fluid (CSF) flow pulsatility and, recently, a reversed CSF flow in the aqueduct have been suggested as hallmarks of idiopathic normal pressure hydrocephalus (INPH). However, these findings have not been adequately confirmed. Our objective was to investigate the flow of blood and CSF in INPH, as compared to healthy elderly, in order to clarify which flow parameters are related to the INPH pathophysiology.

Materials and Methods: Sixteen INPH patients (73 years) and 35 healthy subjects (72 years) underwent phase-contrast magnetic resonance imaging (MRI). Measurements included aqueduct and cervical CSF flow, total arterial inflow (tCBF; i.e. carotid + vertebral arteries), and internal jugular vein flow. Flow pulsatility, net flow, and flow delays were compared (multiple linear regression, correcting for sex and age).

Results: Aqueduct stroke volume was higher in INPH than healthy (148±95 vs 90±50 mL, P<.05). Net aqueduct CSF flow was similar in magnitude and direction. The cervical CSF stroke volume was lower (P<.05). The internal carotid artery net flow was lower in INPH (P<.05), although tCBF was not. No differences were found in internal jugular vein flow or flow delays.

Conclusions: The typical flow of blood and CSF in INPH was mainly characterized by increased CSF pulsatility in the aqueduct and reduced cervical CSF pulsatility. The direction of mean net aqueduct CSF flow was from the third to the fourth ventricle. Our findings may reflect the altered distribution of intracranial CSF volume in INPH, although the causality of these relationships is unclear.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2017
Keywords
aqueduct flow, cerebral blood flow, cerebrospinal fluid, dementia, normal pressure hydrocephalus, phase-contrast magnetic resonance imaging
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-131143 (URN)10.1111/ane.12636 (DOI)000400156400012 ()27388230 (PubMedID)
Funder
Swedish Research Council, 221-2011-5216
Available from: 2017-02-06 Created: 2017-02-06 Last updated: 2018-06-09Bibliographically approved
Holmlund, P., Johansson, E., Qvarlander, S., Wåhlin, A., Ambarki, K., Koskinen, L.-O. D., . . . Eklund, A. (2017). Human jugular vein collapse in the upright posture: implications for postural intracranial pressure regulation. Fluids and Barriers of the CNS, 14, Article ID 17.
Open this publication in new window or tab >>Human jugular vein collapse in the upright posture: implications for postural intracranial pressure regulation
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2017 (English)In: Fluids and Barriers of the CNS, ISSN 2045-8118, E-ISSN 2045-8118, Vol. 14, article id 17Article in journal (Refereed) Published
Abstract [en]

Background: Intracranial pressure (ICP) is directly related to cranial dural venous pressure (P-dural). In the upright posture, P-dural is affected by the collapse of the internal jugular veins (IJVs) but this regulation of the venous pressure has not been fully understood. A potential biomechanical description of this regulation involves a transmission of surrounding atmospheric pressure to the internal venous pressure of the collapsed IJVs. This can be accomplished if hydrostatic effects are cancelled by the viscous losses in these collapsed veins, resulting in specific IJV cross-sectional areas that can be predicted from flow velocity and vessel inclination. Methods: We evaluated this potential mechanism in vivo by comparing predicted area to measured IJV area in healthy subjects. Seventeen healthy volunteers (age 45 +/- 9 years) were examined using ultrasound to assess IJV area and flow velocity. Ultrasound measurements were performed in supine and sitting positions. Results: IJV area was 94.5 mm(2) in supine and decreased to 6.5 +/- 5.1 mm(2) in sitting position, which agreed with the predicted IJV area of 8.7 +/- 5.2 mm(2) (equivalence limit +/- 5 mm(2), one-sided t tests, p = 0.03, 33 IJVs). Conclusions: The agreement between predicted and measured IJV area in sitting supports the occurrence of a hydrostatic-viscous pressure balance in the IJVs, which would result in a constant pressure segment in these collapsed veins, corresponding to a zero transmural pressure. This balance could thus serve as the mechanism by which collapse of the IJVs regulates P-dural and consequently ICP in the upright posture.

Place, publisher, year, edition, pages
BioMed Central, 2017
Keywords
Jugular vein, Collapse, Intracranial pressure, Posture, Physiology
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-137632 (URN)10.1186/s12987-017-0065-2 (DOI)000403482600001 ()28623925 (PubMedID)
Available from: 2017-07-18 Created: 2017-07-18 Last updated: 2019-03-06Bibliographically approved
Holmlund, P., Johansson, E., Qvarlander, S., Wåhlin, A., Ambarki, K., Koskinen, L.-O. D., . . . Eklund, A. (2017). Jugular vein collapse in upright and its relation to intracranial pressure regulation. Paper presented at 28th International Symposium on Cerebral Blood Flow, Metabolism and Function / 13th International Conference on Quantification of Brain Function with PET, APR 01-04, 2017, Int Soc Cerebral Blood Flow & Metab, Berlin, GERMANY. Journal of Cerebral Blood Flow and Metabolism, 37, 297-297
Open this publication in new window or tab >>Jugular vein collapse in upright and its relation to intracranial pressure regulation
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2017 (English)In: Journal of Cerebral Blood Flow and Metabolism, ISSN 0271-678X, E-ISSN 1559-7016, Vol. 37, p. 297-297Article in journal, Meeting abstract (Refereed) Published
Place, publisher, year, edition, pages
SAGE PUBLICATIONS INC, 2017
National Category
Physiology Neurosciences
Identifiers
urn:nbn:se:umu:diva-136208 (URN)000400157400425 ()
Conference
28th International Symposium on Cerebral Blood Flow, Metabolism and Function / 13th International Conference on Quantification of Brain Function with PET, APR 01-04, 2017, Int Soc Cerebral Blood Flow & Metab, Berlin, GERMANY
Note

Supplement: 1 Meeting Abstract: PS03-082

Available from: 2017-07-03 Created: 2017-07-03 Last updated: 2019-05-20Bibliographically approved
Zarrinkoob, L., Ambarki, K., Wåhlin, A., Birgander, R., Carlberg, B., Eklund, A. & Malm, J. (2016). Aging alters the dampening of pulsatile blood flow in cerebral arteries. Journal of Cerebral Blood Flow and Metabolism, 36(9), 1519-1527
Open this publication in new window or tab >>Aging alters the dampening of pulsatile blood flow in cerebral arteries
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2016 (English)In: Journal of Cerebral Blood Flow and Metabolism, ISSN 0271-678X, E-ISSN 1559-7016, Vol. 36, no 9, p. 1519-1527Article in journal (Refereed) Published
Abstract [en]

Excessive pulsatile flow caused by aortic stiffness is thought to be a contributing factor for several cerebrovascular diseases. The main purpose of this study was to describe the dampening of the pulsatile flow from the proximal to the distal cerebral arteries, the effect of aging and sex, and its correlation to aortic stiffness. Forty-five healthy elderly (mean age 71 years) and 49 healthy young (mean age 25 years) were included. Phase-contrast magnetic resonance imaging was used for measuring blood flow pulsatility index and dampening factor (proximal artery pulsatility index/distal artery pulsatility index) in 21 cerebral and extra-cerebral arteries. Aortic stiffness was measured as aortic pulse wave velocity. Cerebral arterial pulsatility index increased due to aging and this was more pronounced in distal segments of cerebral arteries. There was no difference in pulsatility index between women and men. Dampening of pulsatility index was observed in all cerebral arteries in both age groups but was significantly higher in young subjects than in elderly. Pulse wave velocity was not correlated with cerebral arterial pulsatility index. The increased pulsatile flow in elderly together with reduced dampening supports the pulse wave encephalopathy theory, since it implies that a higher pulsatile flow is reaching distal arterial segments in older subjects.

National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:umu:diva-126505 (URN)10.1177/0271678X16629486 (DOI)000382996800004 ()26823470 (PubMedID)
Available from: 2016-10-27 Created: 2016-10-10 Last updated: 2019-05-09Bibliographically approved
Dunås, T., Wåhlin, A., Ambarki, K., Zarrinkoob, L., Birgander, R., Malm, J. & Eklund, A. (2016). Automatic labeling of cerebral arteries in magnetic resonance angiography. Magnetic Resonance Materials in Physics, Biology and Medicine, 29(1), 39-47
Open this publication in new window or tab >>Automatic labeling of cerebral arteries in magnetic resonance angiography
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2016 (English)In: Magnetic Resonance Materials in Physics, Biology and Medicine, ISSN 0968-5243, E-ISSN 1352-8661, Vol. 29, no 1, p. 39-47Article in journal (Refereed) Published
Abstract [en]

In order to introduce 4D flow magnetic resonance imaging (MRI) as a standard clinical instrument for studying the cerebrovascular system, new and faster postprocessing tools are necessary. The objective of this study was to construct and evaluate a method for automatic identification of individual cerebral arteries in a 4D flow MRI angiogram. Forty-six elderly individuals were investigated with 4D flow MRI. Fourteen main cerebral arteries were manually labeled and used to create a probabilistic atlas. An automatic atlas-based artery identification method (AAIM) was developed based on vascular-branch extraction and the atlas was used for identification. The method was evaluated by comparing automatic with manual identification in 4D flow MRI angiograms from 67 additional elderly individuals. Overall accuracy was 93 %, and internal carotid artery and middle cerebral artery labeling was 100 % accurate. Smaller and more distal arteries had lower accuracy; for posterior communicating arteries and vertebral arteries, accuracy was 70 and 89 %, respectively. The AAIM enabled fast and fully automatic labeling of the main cerebral arteries. AAIM functionality provides the basis for creating an automatic and powerful method to analyze arterial cerebral blood flow in clinical routine.

Keywords
Magnetic resonance angiography, Cerebral angiography, Circle of Willis, Atlases as topic, Automatic data processing
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:umu:diva-117830 (URN)10.1007/s10334-015-0512-5 (DOI)000370159800005 ()
Available from: 2016-04-05 Created: 2016-03-04 Last updated: 2018-06-07Bibliographically approved
Vågberg, M., Ambarki, K., Lindqvist, T., Birgander, R. & Svenningsson, A. (2016). Brain parenchymal fraction in an age-stratified healthy population: determined by MRI using manual segmentation and three automated segmentation methods. Journal of neuroradiology, 43(6), 384-391
Open this publication in new window or tab >>Brain parenchymal fraction in an age-stratified healthy population: determined by MRI using manual segmentation and three automated segmentation methods
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2016 (English)In: Journal of neuroradiology, ISSN 0150-9861, E-ISSN 1773-0406, Vol. 43, no 6, p. 384-391Article in journal (Refereed) Published
Abstract [en]

BACKGROUND AND PURPOSE: Brain atrophy is a prominent feature in many neurodegenerative diseases, such as multiple sclerosis, but age-related decrease of brain volume occurs regardless of pathological neurodegeneration. Changes in brain volume can be described by use of the brain parenchymal fraction (BPF), most often defined as the ratio of total brain parenchyma to total intracranial space. The BPF is of interest both in research and in clinical practice. To be able to properly interpret this variable, the normal range of BPF must be known. The objective of this study is to present normal values for BPF, stratified by age, and compare manual BPF measurement to three automated methods. MATERIALS AND METHODS: The BPFs of 106 healthy individuals aged 21 to 85 years were determined by the automated segmentation methods SyMap, VBM8 and SPM12. In a subgroup of 54 randomly selected individuals, the BPF was also determined by manual segmentation. RESULTS: The median (IQR) BPFs of the whole study population were 0.857 (0.064), 0.819 (0.028) and 0.784 (0.073) determined by SyMap, VBM8 and SPM12, respectively. The BPF decreased with increasing age. The correlation coefficients between manual segmentation and SyMap, VBM8 and SPM12 were 0.93 (P<0.001), 0.77 (P<0.001) and 0.56 (P<0.001), respectively. CONCLUSIONS: There was a clear relationship between increasing age and decreasing BPF. Knowledge of the range of normal BPF in relation to age group will help in the interpretation of BPF data. The automated segmentation methods displayed varying degrees of similarity to the manual reference, with SyMap being the most similar.

Place, publisher, year, edition, pages
Masson Editeur, 2016
Keywords
BPF, Brain atrophy, SPM, SyMap, VBM
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-128693 (URN)10.1016/j.neurad.2016.08.002 (DOI)000391158900004 ()27720265 (PubMedID)2-s2.0-84995584817 (Scopus ID)
Available from: 2016-12-12 Created: 2016-12-12 Last updated: 2018-06-09Bibliographically approved
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