Evaluation of the INTERPRET decision-support system: can it improve the diagnostic value of magnetic resonance spectroscopy of the brain?

PURPOSE: We evaluated in a clinical setting the INTERPRET decision-support system (DSS), a software generated to aid in MRS analysis to achieve a specific diagnosis for brain lesions. METHODS: The material consisted of 100 examinations of focal intracranial lesions with confirmed diagnoses. MRS was obtained at 1.5 T using TE 20-30 ms. Data were processed with the LCModel for conventional analysis. The INTERPRET DSS 3.1. was used to obtain specific diagnoses. MRI and MRS were reviewed by one interpreter. DSS analysis was made by another interpreter, in 80 cases by two interpreters. The diagnoses were compared with the definitive diagnoses. For comparisons between DSS, conventional MRS analysis, and MRI, the diagnoses were categorised: high-grade tumour, low-grade tumour, non-neoplastic lesion. RESULTS: Interobserver agreement in choosing the diagnosis from the INTERPRET database was 75%. The diagnosis was correct in 38/100 cases, incorrect in 57 cases. No good match was found in 5/100 cases. The diagnostic category was correct with DSS/conventional MRS/MRI in 67/58/52 cases, indeterminate in 5/8/20 cases, incorrect in 28/34/28 cases. Results with DSS were not significantly better than with conventional MRS analysis. All definitive diagnoses did not exist in the INTERPRET database. In the 61 adult patients with the diagnosis included in the database, DSS/conventional MRS/MRI yielded a correct diagnosis category in 48/32/29 cases (DSS vs conventional MRS: p = 0.002, DSS vs MRI: p = 0.0004). CONCLUSION: Use of the INTERPRET DSS did not improve MRS categorisation of the lesions in the unselected clinical cases. In adult patients with lesions existing in the INTERPRET database, DSS improved the results, which indicates the potential of this software with an extended database.

Guidelines for the use of magnetic resonance imaging in diagnosing and monitoring the treatment of multiple sclerosis: recommendations of the Swedish Multiple Sclerosis Association and the Swedish Neuroradiological Society.

Multiple sclerosis (MS) is associated with inflammatory lesions in the brain and spinal cord. The detection of such inflammatory lesions using magnetic resonance imaging (MRI) is important in the consideration of the diagnosis and differential diagnoses of MS, as well as in the monitoring of disease activity and predicting treatment efficacy. Although there is strong evidence supporting the use of MRI for both the diagnosis and monitoring of disease activity, there is a lack of evidence regarding which MRI protocols to use, the frequency of examinations, and in what clinical situations to consider MRI examination. A national workshop to discuss these issues was held in Stockholm, Sweden, in August 2015, which resulted in a Swedish consensus statement regarding the use of MRI in the care of individuals with MS. The aim of this consensus statement is to provide practical advice for the use of MRI in this setting. The recommendations are based on a review of relevant literature and the clinical experience of workshop attendees. It is our hope that these recommendations will benefit individuals with MS and guide healthcare professionals responsible for their care.

Magnetic resonance imaging-estimated placental perfusion in fetal growth assessment.

OBJECTIVE: To evaluate in-vivo placental perfusion fraction, estimated by magnetic resonance imaging (MRI), as a marker of placental function. METHODS: A study population of 35 pregnant women, of whom 13 had pre-eclampsia (PE), were examined at 22-40 weeks' gestation. Within a 24-h period, each woman underwent an MRI diffusion-weighted sequence (from which we calculated the placental perfusion fraction), venous blood sampling and an ultrasound examination including estimation of fetal weight, amniotic fluid index and Doppler velocity measurements. The perfusion fractions in pregnancies with and without fetal growth restriction were compared and correlations between the perfusion fraction and ultrasound estimates and plasma markers were estimated using linear regression. The associations between the placental perfusion fraction and ultrasound estimates were modified by the presence of PE (P < 0.05) and therefore we included an interaction term between PE and covariates in the models. RESULTS: The median placental perfusion fractions in pregnancies with and without fetal growth restriction were 21% and 32%, respectively (P = 0.005). The correlations between placental perfusion fraction and ultrasound estimates and plasma markers were highly significant (P = 0.002 and P = 0.0001, respectively). The highest coefficient of determination (R(2) = 0.56) for placental perfusion fraction was found for a model that included pulsatility index in the ductus venosus, plasma level of soluble fms-like tyrosine kinase-1, estimated fetal weight and presence of PE. CONCLUSION: The placental perfusion fraction has the potential to contribute to the clinical assessment of cases with placental insufficiency.

A putative vulnerability locus to multiple sclerosis maps to 5p14-p12 in a region syntenic to the murine locus Eae2.

Multiple sclerosis (MS) is a chronic inflammatory disorder characterized by multifocal damage of myelin in the central nervous system (CNS). The prevalence of this putative autoimmune disease is 0.1% in individuals of northern European origin. Family, adoption and twin studies implicate genetic factors in the aetiology. MS is widely speculated to be a multifactorial disorder with a complex mode of inheritance. Despite many studies of candidate genes, only an association with HLA-DR2-DQ6 has been generally detected, and the number of susceptibility genes remains unknown. The chronic variant of experimental allergic encephalomyelitis (EAE), a T-cell mediated autoimmune disease in rodents, represents a relevant animal model for MS given the chronic relapsing disease course and inflammatory changes of CNS observed in these demyelinating disorders. Susceptibility to EAE is also influenced by the major histocompatibility complex (MHC). Human syntenic regions to murine loci predisposing to EAE were tested as candidate regions for genetic susceptibility of MS. Three chromosomal regions (1p22-q23, 5p14-p12 and Xq13.2-q22) were screened in 21 Finnish multiplex MS families most originating from a high risk region in western Finland. Several markers yielded positive lod scores on 5p14-p12, syntenic to the murine locus Eae2. Our data provide evidence for a predisposing locus for MS on 5p14-p12.

High Intravascular Signal Arterial Transit Time Artifacts Have Negligible Effects on Cerebral Blood Flow and Cerebrovascular Reserve Capacity Measurement Using Single Postlabel Delay Arterial Spin-Labeling in Patients with Moyamoya Disease.

BACKGROUND AND PURPOSE: Arterial spin-labeling-derived CBF values may be affected by arterial transit time artefacts. Thus, our aim was to assess to what extent arterial spin-labeling-derived CBF and cerebrovascular reserve capacity values in major vascular regions are overestimated due to the arterial transit time artifacts in patients with Moyamoya disease. MATERIALS AND METHODS: Eight patients with Moyamoya disease were included before or after revascularization surgery. CBF maps were acquired using a 3D pseudocontinuous arterial spin-labeling sequence, before and 5, 15, and 25 minutes after an IV acetazolamide injection and were registered to each patient's 3D-T1-weighted images. Vascular regions were defined by spatial normalization to a Montreal Neurological Institute-based vascular regional template. The arterial transit time artifacts were defined as voxels with high signal intensity corresponding to the right tail of the histogram for a given vascular region, with the cutoff selected by visual inspection. Arterial transit time artifact maps were created and applied as masks to exclude arterial transit time artifacts on CBF maps, to create corrected CBF maps. The cerebrovascular reserve capacity was calculated as CBF after acetazolamide injection relative to CBF at baseline for corrected and uncorrected CBF values, respectively. RESULTS: A total of 16 examinations were analyzed. Arterial transit time artifacts were present mostly in the MCA, whereas the posterior cerebral artery was generally unaffected. The largest differences between corrected and uncorrected CBF and cerebrovascular reserve capacity values, reported as patient group average ratio and percentage point difference, respectively, were 0.978 (95% CI, 0.968-0.988) and 1.8 percentage points (95% CI, 0.3-3.2 percentage points). Both were found in the left MCA, 15 and 5 minutes post-acetazolamide injection, respectively. CONCLUSIONS: Arterial transit time artifacts have negligible overestimation effects on calculated vascular region-based CBF and cerebrovascular reserve capacity values derived from single-delay 3D pseudocontinuous arterial spin-labeling.

Venous saturation slab causes overestimation of stenosis length in two-dimensional time-of-flight magnetic resonance angiography.

BACKGROUND: The use of downstream saturation slabs in two-dimensional time-of-flight magnetic resonance angiography (2D TOF MRA) of the arterial system eliminates signal from regions with countercurrent flow, as seen in veins, but possibly also beyond arterial stenoses because of flow turbulence. PURPOSE: To investigate the contribution of a downstream saturation slab to signal intensity (SI) loss beyond stenoses at 2D TOF MRA. MATERIAL AND METHODS: 2D TOF MRA was performed on a bifurcation phantom with a tight stenosis at 1.5T during pulsatile flow. Qualitative and quantitative evaluations of stenosis delineation were performed with different echo times (TE) (3.7 or 7.0 ms), spatial resolution (1 x 1 x 1 or 1 x 1 x 5 mm(3)), and with or without a downstream saturation slab. For reference, a high-resolution contrast-enhanced sequence without flow was obtained. RESULTS: The downstream saturation slab caused severe signal loss immediately distal to the stenosis, causing overestimation of stenosis length. This region corresponded with a region of poststenotic flow jet, where turbulence is expected. With increase in TE, there was some increased SI loss at the level of maximum stenosis. A lower spatial resolution resulted in overall poorer delineation of the stenosis. CONCLUSION: Using clinically relevant sequence parameters, the use of a downstream saturation slab at 2D TOF MRA was found to be a major contributor to signal loss in stenotic regions, which can result in an overestimation of stenosis length.

Kinetic simulation model of protein secretion and accumulation in the cell microcapsules.

BACKGROUND: In cell therapy, microencapsulated cells secrete therapeutic protein, which is further released from the microcapsules. In principle, some secreted, but unreleased, protein may accumulate in the microcapsules. The kinetic simulation model was built to simulate the potential accumulation of the protein in the microcapsules. METHODS: The alginate microcapsules were cross-linked with divalent cations to encapsulate either flourescein isothiocyanate (FITC)-dextrans (molecular weights = 4.3, 10.5, 43 kDa) or retinal pigment epithelial cells (ARPE-19). The cells were genetically engineered to produce secreted alkaline phosphatase (SEAP). SEAP production from the cells was quantified with and without microcapsulation and, finally, the cells were killed with toxin to quantify the secreted but yet unreleased SEAP from the microcapsules. The empirical three-compartment kinetic model was constructed based on the release of FITC-dextrans of different molecular weights from the alginate microcapsules with different pore sizes. Protein secretion from the cells into the microcapsules was added to the model. The impact of the microcapsule wall permeability on the steady-state amounts of secreted protein in the microcapsules and in the hypothetical target compartment in the body was simulated. The simulations were compared to the experimental data from the microencapsulated SEAP secreting ARPE-19 cells. RESULTS: The model and the data show that substantial amounts (10-15 daily doses) of protein may accumulate in the microcapsules with poor wall permeability. At high permeability, the accumulation was insignificant. The pharmacokinetic simulations show that even a 1.5-fold increase in the wall permeability may result in a substantial peak in the drug amount in the target compartment, especially if the elimination rate of the protein is high. CONCLUSIONS: The kinetic simulation model for protein secretion from microcapsulated cells is a useful tool for the early kinetic prediction and risk assessment of cell therapy.

The prevalence and quantification of atherosclerosis in an elderly population assessed by whole-body magnetic resonance angiography.

OBJECTIVE: The principal aim of the present study was to explore the feasibility of using whole-body magnetic resonance angiography to assess atherosclerosis in different vascular territories in a cohort of elderly. METHODS AND RESULTS: Three hundred six 70-year-old subjects (145 women, 161 men) recruited from a population-based cohort study (Prospective Investigation of the Vasculature in Uppsala Seniors, ie, the PIVUS study) underwent 1.5-T whole-body magnetic resonance angiography with gadodiamide. The arteries were divided into 26 segments. In total, 7956 vessel segments were evaluated with 7900 segments (99.3%) possible to evaluate. Of these, 7186 segments (91%) were normal. Luminal narrowing of > or = 50% was observed in 9 (1.5%) of the renal arteries, 12 (1.8%) of the carotid arteries, in 31 segments (1.1%) of the pelvic/upper leg territories, and in 136 segments (6.2%) of territories in the lower leg. Approximately one-third of the sample had no vascular abnormalities, one-third had stenoses of < 50%, and the remainder had stenoses > or = 50% or occlusions. Six subjects (2%) had aortic aneurysms. In subjects without evident vascular disease, 26% had significant vascular abnormalities. CONCLUSIONS: Whole-body magnetic resonance angiography performed with a clinical scanner can be used for quantifying atherosclerosis in different vascular territories in a single examination in an elderly population.

Ankle brachial index <0.9 underestimates the prevalence of peripheral artery occlusive disease assessed with whole-body magnetic resonance angiography in the elderly.

BACKGROUND: Whole-body magnetic resonance angiography (WBMRA) permits noninvasive vascular assessment, which can be utilized in epidemiological studies. PURPOSE: To assess the relation between a low ankle brachial index (ABI) and high-grade stenoses in the pelvic and leg arteries in the elderly. MATERIAL AND METHODS: WBMRA was performed in a population sample of 306 subjects aged 70 years. The arteries below the aortic bifurcation were graded after the most severe stenosis according to one of three grades: 0-49% stenosis, 50-99% stenosis, or occlusion. ABI was calculated for each side. RESULTS: There were assessable WBMRA and ABI examinations in 268 (right side), 265 (left side), and 258 cases (both sides). At least one > or =50% stenosis was found in 19% (right side), 23% (left side), and 28% (on at least one side) of the cases. The corresponding prevalences for ABI <0.9 were 4.5%, 4.2%, and 6.6%. An ABI cut-off value of 0.9 resulted in a sensitivity, specificity, and positive and negative predictive value of 20%, 99%, 83%, and 84% on the right side, and 15%, 99%, 82%, and 80% on the left side, respectively, for the presence of a > or =50% stenosis in the pelvic or leg arteries. CONCLUSION: An ABI <0.9 underestimates the prevalence of peripheral arterial occlusive disease in the general elderly population.

Three-dimensional time-of-flight (3D TOF) magnetic resonance angiography (MRA) and contrast-enhanced MRA of intracranial aneurysms treated with platinum coils.

BACKGROUND: Contrast-enhanced magnetic resonance angiography (CE-MRA) is less prone to flow-related signal intensity loss than three-dimensional time-of-flight (3D TOF) MRA and may therefore be more sensitive for detection of residual patency in platinum coil-treated intracranial aneurysms. PURPOSE: To compare MRA and CE-MRA in the follow-up of intracranial aneurysms treated with platinum coils. MATERIAL AND METHODS: CE-MRA and 3D TOF MRA (pre- and postcontrast injection) of the intracranial vasculature was performed at 1.5T in 38 patients (47 aneurysms) referred for DSA in the follow-up of coiled intracranial aneurysms. RESULTS: DSA showed aneurysm patency in 22/47 investigations. Patent aneurysm components were observed with CE-MRA in 18/22 cases, and with 3D TOF MRA in 21/22 cases. There was no significant difference in patent aneurysm component size between CE-MRA and 3D TOF MRA. In addition, CE-MRA showed six, 3D TOF MRA before contrast injection showed seven, and 3D TOF MRA after contrast injection showed eight cases with patent aneurysm components not observed on DSA. CONCLUSION: 3D TOF MRA was highly sensitive for detection of patent aneurysm components, and at least as sensitive as CE-MRA. Residual aneurysm patency seems to be better visualized with MRA than with DSA in some cases.

Pregnancy hypertensive disease and risk of dementia and cardiovascular disease in women aged 65 years or older: a cohort study.

OBJECTIVE: The primary aim was to study pregnancy hypertensive disease and subsequent risk of dementia. The second aim was to study if the increased risks of cardiovascular disease (CVD) and stroke after pregnancy hypertensive disease persist in an elderly population. DESIGN: Cohort study. SETTING: Sweden. POPULATION OR SAMPLE: 3232 women 65 years or older (mean 71 years) at inclusion. METHODS: Cox proportional hazards regression analyses were used to calculate risks of dementia, CVD and/or stroke for women exposed to pregnancy hypertensive disease. Exposure data were collected from an interview at inclusion during the years 1998-2002. Outcome data were collected from the National Patient Register and Cause of Death Register from the year of inclusion until the end of 2010. Age at inclusion was set as a time-dependent variable, and adjustments were made for body mass index, education and smoking. MAIN OUTCOME MEASURES: Dementia, CVD, stroke. RESULTS: During the years of follow-up, 7.6% of the women exposed to pregnancy hypertensive disease received a diagnosis of dementia, compared with 7.4% among unexposed women (HR 1.19; 95% CI 0.79 to 1.73). The corresponding rates for CVD were 22.9% for exposed women and 19.0% for unexposed women (HR 1.29; 95% CI 1.02 to 1.61), and for stroke 13.4% for exposed women and 10.7% for unexposed women (HR 1.36; 95% CI 1.00 to 1.81). CONCLUSIONS: There was no increased risk of dementia after self-reported pregnancy hypertensive disease in our cohort. We found that the previously reported increased risk of CVD and stroke after pregnancy hypertensive disease persists in an older population.

Dementia among medical inpatients. Evaluation of 2000 consecutive admissions.

Two thousand consecutive patients aged 55 years and older admitted to a department of medicine in a large university hospital were examined for the presence of dementia. The occurrence of moderate and severe dementia was 9.1% for all age groups. It increased from 0.8% in the age group from 55 to 64 years to 31.2% in patients aged 85 years and older. Of the demented patients, 41.4% were delirious at admission, and 24.9% of all delirious patients were demented. Patients with vascular dementia constituted 72.4%, those with primary degenerative dementia 23.0%, and those with specific causes 4.6% of all demented patients. The mean hospitalization time for demented patients was significantly longer, and they needed significantly more daily nursing care, when compared with nondemented patients.

Reappraisal of HLA in multiple sclerosis: close linkage in multiplex families.

Although association between multiple sclerosis (MS) and HLA-DR2,DQw6 has been well documented, family studies have not established linkage to HLA. Here we have (1) carried out an HLA-DQA1, -DQB1 association study in unrelated patients and controls, and (2) analyzed linkage between MS and HLA in multiplex families using both nonparametric and parametric methods. The subjects and families were derived from the genetically homogeneous Finnish population, and 14 of the 21 families came from a high-risk area with exceptional familial clustering of cases. In the association study, the frequencies of the alleles DQA1*0102 and DQB1*0602 (encoding DR2-associated DQw6 antigen) were significantly increased in MS patients compared to controls. In the families, we observed that the segregation of MS with DQA1*0102 and DQB1*0602 was not HLA haplotype specific, i.e., these alleles were frequently transmitted to MS relatives on different parental haplotypes. Consequently, we found strong evidence for linkage between MS and HLA only when the haplotype-independent segregation of the MS-associated alleles was controlled. This observation may partially explain the lack of linkage evidence in previous family studies. The highest LOD scores were obtained to the DQA1 locus (LODmax = 6.43, theta = 0.00). The linkage analyses suggest that both the patients' HLA haplotypes may contribute to MS susceptibility. In one of a patient's haplotypes, the susceptibility locus was closely associated with DQA1*0102 and DQB1*0602, whereas in the other haplotype no association with any of the individual candidate loci was found. These results demonstrate, for the first time, a close linkage between MS and HLA, and raise the possibility of distinct HLA-linked susceptibility genes in MS.

Somatostatin-like immunoreactivity in lumbar cerebrospinal fluid from neurohistologically examined demented patients.

The concentration of somatostatin-like immunoreactivity (SLI) in lumbar cerebrospinal fluid was measured in clinically suspected examples of either Alzheimer's disease (AD) or Pick's disease and controls. No significant correlation was found between the concentration of SLI and the age (22-73 years) of controls. Histological examination of brain material from the demented patients enabled the samples to be divided into AD and examples of clinically suspected AD or Pick's disease without specific histological change. The mean concentration of SLI was only slightly reduced in patients with AD in the presenium compared to control, and was unaltered from control in the examples of AD of senile age. The group of demented patients without specific histological change had a reduced concentration of SLI in lumbar CSF compared to control patients.

Classic amyotrophic lateral sclerosis with dementia.

Documented cases of classic amyotrophic lateral sclerosis (ALS) combined with severe dementia are few and come from the isolated populations of the Western Pacific. In this report, three women had a clinically and neuropathologically documented combination of ALS and dementia. In all cases the symptoms and signs of ALS were mainly bulbar. In two of them dementia appeared first, followed by ALS. At autopsy, there was a marked discrepancy between the severe degree of dementia of Alzheimer's type and the sight nonspecific neuropathologic findings without Alzheimer's changes. Our cases bear a close resemblance to recently published Japanese cases. It may be concluded that the combination of sporadic ALS and progressive dementia seems to be a clinical entity without consistent neuropathologic changes and that it also occurs in the western countries.

Prevalence of severe dementia in Finland.

A sample of 8,000 subjects to represent the population of Finland aged 30 years and over was used to identify patients with severe dementia; 141 cases were found. The prevalence of all types of severe dementia was 1.8% in the whole study population and 6.7% in the population aged 65 years and over. The prevalence increased with advancing age to 17.3% in the age group 85 years and over. Primary degenerative dementia constituted 50% of all cases; multi-infarct and combined dementia, 39%; and secondary dementia, 11%. Fifty-seven percent of the patients lived in institutions.

Immune system genes in multiple sclerosis: genetic association and linkage analyses on TCR beta, IGH, IFN-gamma and IL-1ra/IL-1 beta loci.

The role of genetic factors in the etiology of multiple sclerosis (MS) has been clearly demonstrated but the loci determining susceptibility to this disease remain largely unidentified. A contribution from several immune system genes has been suggested based on animal models and association/linkage analyses on MS patients and families. With the exception of the findings from the HLA complex, studies on candidate immune system genes have provided controversial results. Here we have performed genetic association and linkage analyses on four chromosomal regions containing immune system genes. A possible role for each of these loci in MS has been previously suggested. In data-sets derived from the Finnish population we found no evidence for contribution of the T-cell receptor beta chain (TCR beta chromosome 7q35), immunoglobulin heavy chain (IGH chromosome 14q32), interferon-gamma (IFN-gamma chromosome 12q14-q15) or interleukin-1 receptor antagonist/interleukin-1 beta (IL-1ra/IL-1 beta chromosome 2q14-q21) loci in the genetic susceptibility to MS.