Perivascular Spaces in Old Age: Assessment, Distribution, and Correlation with White Matter Hyperintensities.

BACKGROUND AND PURPOSE: The visual rating scales for perivascular spaces vary considerably. We sought to develop a new scale for visual assessment of perivascular spaces and to further describe their distribution and association with white matter hyperintensities in old age. MATERIALS AND METHODS: This population-based study included 530 individuals who did not have dementia and were not institutionalized (age, ≥60 years or older; mean age, 70.7 years; 58.9% women) who were living in central Stockholm, Sweden. A semiquantitative visual rating scale was developed to score the number and size of visible perivascular spaces in 7 brain regions in each hemisphere. A modified Scheltens visual rating scale was used to assess white matter hyperintensities. RESULTS: The global scores for perivascular spaces ranged from 4-32 for number, 3-22 for size, and 7-54 for the combination of number and size. The weighted κ statistics for the intra- and interrater reliability both were 0.77. The global score for the number of perivascular spaces increased with advancing age (P < .001). The scores for the number of perivascular spaces in the basal ganglia and subinsular regions were significantly correlated with the load of white matter hyperintensities, especially in lobar and deep white matter regions (partial correlation coefficients, >0.223; P < .01). CONCLUSIONS: The new visual rating scale for perivascular spaces shows excellent intra- and interrater reliability. The number of perivascular spaces globally and, especially, in the basal ganglia, is correlated with the load of lobar and deep white matter hyperintensities, supporting the view that perivascular spaces are a marker for cerebral small-vessel disease.

Do cardiovascular risk factors explain the link between white matter hyperintensities and brain volumes in old age? A population-based study.

BACKGROUND AND PURPOSE: White matter hyperintensities (WMHs) and brain atrophy frequently coexist in older people. However, it is unclear whether the association between these two brain lesions is dependent on the aging process, a vascular mechanism or genetic susceptibility. It was therefore investigated whether the association between load of WMHs and brain atrophy measures is related to age, vascular risk factors (VRFs) or the APOE-ε4 allele. METHODS: This population-based study included 492 participants (age ≥60 years, 59.6% women) free of dementia and stroke. Data on demographics, VRFs and APOE genotypes were collected through interviews, clinical examination and laboratory tests. WMHs on magnetic resonance images were assessed using manual visual rating and automatic volumetric segmentation. Hippocampal and ventricular volumes were manually delineated, whereas total gray matter (GM) volume was measured by automatic segmentation. Data were analyzed with multivariate linear regression models. RESULTS: More global WMHs, assessed using either a visual rating scale or a volumetric approach, were significantly associated with lower GM volume and higher ventricular volume; the associations remained significant after adjusting for age, VRFs and the APOE-ε4 allele. In contrast, the association between global WMHs and hippocampal volume was no longer significant after adjusting for age, whereas adjustment for VRFs and APOE-ε4 had no influential effect. CONCLUSION: The association of global WMHs with lower GM volume and higher ventricular volume is independent of age, VRFs and APOE-ε4 allele, suggesting that the process of cerebral microvascular disease and neurodegeneration are associated independently of the normal aging process, vascular mechanisms or genetic susceptibility.

Medial temporal lobe is vulnerable to vascular risk factors in men: a population-based study.

BACKGROUND AND PURPOSE: Vascular risk factors (VRFs) are known to cause cerebral microvascular disease, but evidence supporting an effect of VRFs on regional brain atrophy is mixed. We investigate whether an aggregation of VRFs is associated with volume of hippocampus and entorhinal cortex in elderly people living in the community. METHODS: This cross-sectional study consists of 523 participants (age ≥60 years, 59.3% women) of the SNAC-K Study in central Stockholm, Sweden, who were free of clinical stroke and cognitive impairment. We collected data on VRFs through interviews, clinical examination and inpatient register system. Hippocampal and entorhinal cortex volume was manually measured on magnetic resonance images. Data were analysed with general linear regression models controlling for demographics and total intracranial volume. RESULTS: In men, high total cholesterol and diabetes were significantly or marginally associated with smaller hippocampus and entorhinal cortex; when current smoking, binge alcohol drinking, high cholesterol and diabetes were aggregated, an increasing number of VRFs were significantly associated with decreasing volume of hippocampus and entorhinal cortex (P for linear trend <0.01). In women, none of individual VRFs or their aggregation was significantly associated with the volume of these brain regions, except former smoking that was significantly associated with a larger volume of these regions. CONCLUSIONS: Aggregation of VRFs is associated with reduced hippocampal and entorhinal cortex volume in apparently healthy elderly men, but not in women. This implies that in men, the medial temporal lobe is vulnerable to cardiovascular risk factors.

Low levels of high density lipoprotein increase the severity of cerebral white matter changes: implications for prevention and treatment of cerebrovascular diseases.

BACKGROUND AND PURPOSE: Cerebral White matter changes (WMC) are a frequent finding on CT and MRI scans of elderly individuals, particularly in those with vascular risk factors, cerberovascular disease, and cognitive impairment. METHODS: 56 subjects were included in the study after the review of reports of more than 200 consecutive brain Computerized Tomography (CT) and magnetic resonance imaging (MRI) examinations from the out-patient and in-patient units of the Department of Geriatric Medicine at Karolinska University Hospital, Huddinge during 2001-2002. MRI was performed using a 1.5 T system and WMC lesions were graded 1-3 using a visual scale. Total-cholesterol (TC), high density lipoprotein (HDL), low density lipoprotein (LDL) and triglyceride (TG) levels were determined using enzymatic techniques after 12 hours overnight fasting. Apo E genotyping was performed as described. RESULTS: Low HDL levels were associated with higher severity of WMC on MRI (p=0.002). Subjects with the Apo E4 allele had higher LDL (p=0.02) and apoB levels (p=0.005). The presence of the Apo E4 allele was higher in the group of subjects with severe WMC (grade 3). However, there was no statistically significant group difference in severity of WMC lesions between carriers and non-carriers of Apo E4 allele. CONCLUSIONS: Low HDL is strongly associated with adverse coronary and cerebrovascular outcomes. Our results indicate that low HDL levels are also associated with more severe WMC lesions on MRI. Dietary or medical adjustment of HDL levels could have important implications for treatment and prevention of cerebral WMC, cerebrovascular and neurodegenerative diseases such as stroke and dementia.

Medial temporal lobe atrophy increases the specificity of cerebrospinal fluid biomarkers in Alzheimer disease with minor cerebrovascular changes.

BACKGROUND: Although cerebrospinal fluid (CSF) biomarkers and medial temporal lobe atrophy (MTA) contribute to the diagnosis of Alzheimer disease (AD), they may not be specific. Relatively little is known about how they correlate with each other. PURPOSE: To identify the validity of the radiological linear measurements of brain atrophy in AD diagnosis by examining the correlation with CSF biomarkers and by examining if specificity could be improved in classification of AD from controls, when the linear measurements are combined with the CSF biomarkers. MATERIAL AND METHODS: 59 controls (20 male/39 female, age 73+/-8 years), 162 pure AD patients (49/113, 74+/-7 years), and 86 AD patients with minor cerebrovascular changes (CVC) (31/55, 77+/-5 years), aged between 52 and 94 years, were recruited from the Malmo Alzheimer Study. AD patients were subgrouped into "pure AD" and "AD + CVC" in order to clarify the possible influence of CVC on atrophy or CSF biomarkers in AD patients. Abeta42, T-tau, and P-tau in CSF were examined. Computed tomography (CT) linear measurements were performed, which included temporal horn ratio and suprasellar cistern ratio that reflect MTA. RESULTS: Compared with the 14 significant correlations between the CT measurements and three CSF biomarkers in the pure AD group, there was only one significant correlation in the AD + CVC group and one in the control group. In particular, P-tau correlates with temporal horn ratio only in pure AD. When the CT measurements were added with CSF biomarkers as independent variables in discriminant analysis, the percentage of correct classification of AD + CVC from controls increased from 79.5% (only CSF biomarkers) to 84.6% (combined CT measurements with CSF biomarkers). However, little was changed in the pure AD group. CONCLUSION: P-tau correlates with the linear CT measure of MTA only in pure AD without CVC. Combined with the measure of MTA, the specificity of CSF biomarkers can be increased, but only in AD + CVC. The linear measurements of MTA are of value in AD diagnosis.

White matter changes in dementia: does radiology matter?

White matter changes are frequently seen on MRI in elderly patients. The significance of these changes is still debated. The origin of white matter changes is heterogeneous but the majority are due to arteriosclerosis in brain vessels. The clinical consequence of the presence of white matter changes in relation to dementia is still unclear. Lately, however, many studies have found a relation between the presence and the degree of white matter changes and cognitive dysfunction. This is most obvious in vascular dementia, but has also been suggested to be of importance in Alzheimer's disease. In this review we discuss the background of these changes and the clinical consequences of them in relation to cognitive disorders.

Multiple sclerosis: a study of chemokine receptors and regulatory T cells in relation to MRI variables.

Magnetic resonance imaging (MRI) remains the most valuable tool for monitoring disease activity and progression in patients with multiple sclerosis (MS), a chronic demyelinating disease of the central nervous system (CNS) with presumably autoimmune etiology. Chemokine receptors have been implicated in MS as key molecules directing inflammatory cells into the CNS. Regulatory (CD4+CD25+) T cells (Tr cells) are important in suppressing autoimmunity, and their absolute or functional deficit could be expected in MS. In the present study, venous blood was obtained from MS patients concurrent with MRI examination of the brain, and expression of chemokine receptors CCR1, CCR2, CCR5, CXCR3 and CXCR4 by CD4 T cells and monocytes, proportions of Tr cells, as well as expression of CD45RO, CD95, CTLA-4, HLA-DR and interleukin (IL)-10 by Tr cells and non-Tr (CD25-) CD4 T cells was analyzed by flow cytometry. Surface expression of CXCR3 by CD4 T cells was downregulated in the group of patients with high lesion load (LL) on T2-weighted images and gadolinium (Gd)-enhancing lesions on T1-weighted images, compared to the group with high LL and no Gd-enhancing lesions, and to the group with low LL, suggesting internalization of CXCR3 due to the release of its chemokine ligand (IP-10/CXCL10) from active MS lesions. Proportions of Tr cells amongst all CD4 T cells, and expression of IL-10 by Tr cells were increased in the patients with high LL and Gd-enhancing lesions. These results suggest that there is correlation between MRI parameters, chemokine receptor expression and the status of circulating Tr cells in MS, but further studies need to discriminate between pathogenetically relevant and bystander phenomena.

Can the site of brain lesion predict improved motor function after low-TENS treatment on the post-stroke paretic arm?

OBJECTIVES: Previous reports suggest that afferent stimulation improves arm motor function in patients suffering from stroke. The aim of this pilot study was to test the hypothesis that the brain lesion location determines the response to low-frequency (1.7 Hz) transcutaneous electric nerve stimulation (Low-TENS) therapy. DESIGN: Magnetic resonance imaging (MRI) was performed on 14 patients who had previously received Low-TENS on the paretic arm after stroke. METHODS: MR images were classified with two different methods. First, lesions in the cortical and the subcortical areas were registered. Secondly, any change in a described periventricular white matter (PVWM) area was recorded. Interactions between the lesion site, as detected by MRI, and response to Low-TENS treatment were analysed. RESULTS: Arm motor function after Low-TENS treatment in relation to lesion in different brain areas showed that absence of lesions in the PVWM area increased the possibility for improved motor capacity after afferent stimulation. CONCLUSIONS: The site of lesion may play a role in prognosis/outcome after Low-TENS treatment but this hypothesis should be further tested in a larger prospective study.

A new rating scale for age-related white matter changes applicable to MRI and CT.

BACKGROUND AND PURPOSE: MRI is more sensitive than CT for detection of age-related white matter changes (ARWMC). Most rating scales estimate the degree and distribution of ARWMC either on CT or on MRI, and they differ in many aspects. This makes it difficult to compare CT and MRI studies. To be able to study the evolution and possible effect of drug treatment on ARWMC in large patient samples, it is necessary to have a rating scale constructed for both MRI and CT. We have developed and evaluated a new scale and studied ARWMC in a large number of patients examined with both MRI and CT. METHODS: Seventy-seven patients with ARWMC on either CT or MRI were recruited and a complementary examination (MRI or CT) performed. The patients came from 4 centers in Europe, and the scans were rated by 4 raters on 1 occasion with the new ARWMC rating scale. The interrater reliability was evaluated by using kappa statistics. The degree and distribution of ARWMC in CT and MRI scans were compared in different brain areas. RESULTS: Interrater reliability was good for MRI (kappa=0.67) and moderate for CT (kappa=0.48). MRI was superior in detection of small ARWMC, whereas larger lesions were detected equally well with both CT and MRI. In the parieto-occipital and infratentorial areas, MRI detected significantly more ARWMC than did CT. In the frontal area and basal ganglia, no differences between modalities were found. When a fluid-attenuated inversion recovery sequence was used, MRI detected significantly more lesions than CT in frontal and parieto-occipital areas. No differences were found in basal ganglia and infratentorial areas. CONCLUSIONS: We present a new ARWMC scale applicable to both CT and MRI that has almost equal sensitivity, except for certain regions. The interrater reliability was slightly better for MRI, as was the detectability of small lesions.

White matter lesions impair initiation of FAS flow.

Word fluency performance is known to rely on left frontal cortical regions and has also been shown to be affected by lesions in the white matter, which may be seen as white matter hyperintensities (WMH) on magnetic resonance imaging. However, word fluency may be divided into two independent components, initial and late performance, separated in time [J Clin Exp Neuropsychol 1998;20:137-143]. The purpose of the current study was to investigate the relationship between the two components of FAS fluency performance and WMH. Patients varying in degree of memory impairment participated: Alzheimer's disease, mild cognitive impairment and subjective memory disorder. WMH were rated with the Scheltens scale in the periventricular and deep subcortical areas. Results demonstrated that WMH in this sample of patients may be summarized in two indices according to a principal factor analysis, one anterior factor mainly related to WMH in the frontal lobes and adjacent to ventricles, and a second posterior factor related to parietal and occipital WMH. The initial FAS performance was related to anterior WMH, in particular left frontal or lateral periventricular hyperintensities, whereas the late FAS performance was not related to any index of WMH.

White matter lesions in dementia: an MRI study on blood-brain barrier dysfunction.

White matter lesions (WMLs) and blood-brain barrier (BBB) dysfunction are common in dementia. Both conditions may be a consequence of small-vessel disease, in which case the BBB damage would be suspected to be located to the WMLs. To further evaluate the nature of WMLs in dementia we examined 10 demented patients with WMLs, including 5 cases with elevated CSF/serum albumin ratios as an indication of BBB damage. An optimised gadolinium (Gd)-enhanced MRI technique was used including a double dose of Gd, a 30-min scan time after injection and analysis of the MR signal in the WMLs as a function over time. Results showed no significant changes in MR signal in the WMLs after contrast administration. We conclude that WMLs are not connected to BBB damage to such a degree that is detectable with this method and that the elevated CSF albumin might have another origin.

Contrast-enhanced MRI of white matter lesions in patients with blood-brain barrier dysfunction.

White matter lesions (WMLs) and blood-brain barrier (BBB) dysfunction are common in dementia. Both conditions may be a consequence of small-vessel disease, in which case the BBB damage could be suspected to be located to the WMLs. Magnetic resonance imaging (MRI) can be used to show WMLs as well as to detect BBB damage when using an intravenous contrast agent, gadolinium. We examined 10 demented patients with WMLs, including 5 cases with BBB (elevated CSF/serum albumin ratios). Results showed no significant changes in MR signal in the WMLs after contrast administration. We conclude that WMLs are not related to BBB damage to such a degree that is detectable with this method and that the elevated CSF albumin might have another origin.

White matter lesions in Alzheimer patients are influenced by apolipoprotein E genotype.

To analyse the influence of apolipoprotein E (APOE) genotype on the extent of white matter lesions (WMLs) in Alzheimer's disease (AD), we examined 60 AD patients with magnetic resonance imaging. The WMLs were rated visually in different brain regions. The patients with the APOE genotype sigma4/4 had more extensive WMLs in the deep white matter than patients with genotypes sigma3/3 and sigma3/4. There was a correlation with age for WMLs in the deep white matter in patients with the APOE sigma3/3 genotype. In patients carrying at least one sigma4 allele, the WMLs showed no age correlation. The results could imply that in APOE allele sigma4 carriers, the WMLs represent a pathological process related to the aetiology of the disease.

Comparison of the contrast enhancement pattern in two different T1-weighted 3-D sequences in MR imaging of the breast.

PURPOSE: Can a complementary 3-D T1-weighted sequence (MPRAGE) facilitate the evaluation of contrast enhancement in patients with widespread and early contrast enhancement in our standard 3-D T1-weighted FLASH sequence? MATERIAL AND METHODS: Twenty patients with 27 breast lesions were examined with both FLASH and MPRAGE sequences. The MR examinations were reviewed independently by three radiologists. RESULTS: In both the FLASH and MPRAGE sequences, 11 lesions were true-positive. In the FLASH sequence alone, 3 lesions were true-negative and 13 false-positive in comparison to the MPRAGE sequence alone in which 10 lesions were true-negative and 6 false-positive. Seven lesions that were false-positive in the FLASH sequence were true-negative in the MPRAGE sequence: this shows that MPRAGE has the potential to downgrade the false-positive findings found in the FLASH sequence. CONCLUSION: Due to its higher sensitivity, FLASH is the sequence of first choice at routine examination. However, when atypical increased enhancement was found, the addition of the MPRAGE sequence improved the specificity of the MR investigation.

Contrast-enhanced MR imaging as a prognostic indicator of breast cancer.

BACKGROUND: Using contrast-enhanced MR imaging in the diagnosis of breast cancer may provide additional information not only on tumor extension but also on the biological behavior of tumors. Thus certain characteristics such as tumor angiogenesis and the proliferating activity of the tumor, which have been shown to correlate significantly with prognosis, are both potentially amenable to analysis by MR imaging. MATERIAL AND METHODS: We compared contrast enhancement in 50 malignant breast tumors at MR imaging to several prognostic factors, such as tumor size, lymph-node status, histological grade of malignancy, tumor angiogenesis, and proliferating activity as shown by the mitotic count and PCNA immunoreactivity. RESULTS: There was significant correlation between contrast enhancement at MR imaging of breast cancer and both tumor angiogenesis and proliferative cellular activity as shown by PCNA immunoreactivity. Furthermore, there was a correlation between contrast enhancement and tumor malignancy grade as well as tumor invasiveness. CONCLUSION: These observations suggest that contrast enhancement at MR imaging may be influenced by factors that have prognostic value. If this assumption is correct, contrast-enhanced MR imaging may become a valuable prognostic tool in the pre-operative evaluation of breast cancers.

Can a physician recognize an older driver with increased crash risk potential?

OBJECTIVE: To identify factors in a medical examination that distinguish convicted older drivers with traffic violations from other drivers. DESIGN: Matched case-control study. SETTING: Two countries in Sweden. SUBJECTS: Thirty-seven drivers older than age 65, whose driving licenses have been temporarily suspended, each matched to one control subject based on age, sex, type of driving license, year of first license, living area, educational level, and annual distance driven. MEASUREMENTS: Case and control subjects were compared with respect to medical history, medication use, blood tests, drawing and memory tests, Mini-Mental State Examination, medical status findings, visual acuity, and brain imaging procedures. MAIN RESULTS: The group of drivers with suspended driving licenses did not differ from matched controls with respect to visual acuity or presence of cardiovascular diseases. However, persons with suspended driving licenses were more likely than control subjects to have suspected or mild dementia (P < .010) and to perform less well on two easily administrated screening tests: copying a cube (P < .010) and 5-item recall (P < .010). Case subjects with crashes had significantly more cardiovascular diseases than case subjects with other moving violations (P < .050). These case subjects with crashes also had significantly more cognitive impairments than control subjects without crashes as shown by a higher clinical dementia rating score (CDR) (P < .001), lower score on the Mini-Mental State Examination (MMSE) (P < .050), and lower level of performance in the copying task (cube) (P < .050) and 5-item recall test (P < .010). They also had evidence of greater cognitive impairment than those case subjects with other moving violations. CONCLUSIONS: Visual acuity and common medical examination did not distinguish convicted older drivers with crashes or other moving violations from controls. There was evidence that even mild cognitive impairment contributed to the risk of losing a driving license because of crashes.

Sensitivity and specificity of MR mammography with histopathological correlation in 250 breasts.

PURPOSE: The aim of our prospective study was to determine the diagnostic accuracy of MR mammography (MRM) in detecting malignant disease. MATERIAL AND METHODS: In 231 consecutive patients scheduled for surgery because of mammographic or palpable lesions suspected of malignancy, the breasts were examined with T1-weighted transversal images using a 3-D fast low angle shot (FLASH) sequence. One pre- and 2 post-contrast images were obtained. Histological examination of the surgical specimens showed carcinoma in 155 breasts, of which 138 were invasive and 17 in situ. RESULTS: MRM detected 144 of the 155 malignancies and was false-negative in 11 cases. Eight of these MRM-missed tumours were invasive and 3 were in situ cancers. Benign lesions were found at microscopy in 95 breasts, of which MRM correctly diagnosed 69. The cellular composition of the 26 false-positive lesions (myxomatous stromal change, high vascularity, and epithelial or apocrine hyperplasia) might explain the false positivity. The sensitivity and specificity of MRM were 93% and 73% respectively. CONCLUSION: MRM should be interpreted with caution, and supplemented with e.g. mammography and ultrasonography.