Psychosocial factors and hippocampal subfields: The Medea-7T study.

Specific subfields within the hippocampus have shown vulnerability to chronic stress, highlighting the importance of looking regionally within the hippocampus to understand the role of psychosocial factors in the development of neurodegenerative diseases. A systematic review on psychosocial factors and hippocampal subfield volumes was performed and showed inconsistent results, highlighting the need for future studies to explore this relationship. The current study aimed to explore the association of psychosocial factors with hippocampal (subfield) volumes, using high-field 7T MRI. Data were from the Memory Depression and Aging (Medea)-7T study, which included 333 participants without dementia. Hippocampal subfields were automatically segmented from T2-weighted images using ASHS software. Generalized linear models accounting for correlated outcomes were used to assess the association between subfields (i.e., entorhinal cortex, subiculum, Cornu Ammonis [CA]1, CA2, CA3, dentate gyrus, and tail) and each psychosocial factor (i.e., depressive symptoms, anxiety symptoms, childhood maltreatment, recent stressful life events, and social support), adjusted for age, sex, and intracranial volume. Neither depression nor anxiety was associated with specific hippocampal (subfield) volumes. A trend for lower total hippocampal volume was found in those reporting childhood maltreatment, and a trend for higher total hippocampal volume was found in those who experienced a recent stressful life event. Among subfields, low social support was associated with lower volume in the CA3 (B = -0.43, 95% CI: -0.72; -0.15). This study suggests possible differential effects among hippocampal (subfield) volumes and psychosocial factors.

Low-grade carotid artery stenosis is associated with progression of brain atrophy and cognitive decline. The SMART-MR study.

Asymptomatic low-grade carotid artery stenosis (LGCS) is a common finding in patients with manifest arterial disease, however its relationship with brain MRI changes and cognitive decline is unclear. We included 902 patients (58 ± 10 years; 81% male) enrolled in the Second Manifestations of Arterial Disease - Magnetic Resonance (SMART-MR) study without a history of cerebrovascular disease. LGCS was defined as 1-49% stenosis on baseline carotid ultrasound, whereas no LGCS (reference category) was defined as absence of carotid plaque. Brain and white matter hyperintensity (WMH) volumes and cognitive function were measured at baseline and after 4 (n = 480) and 12 years (n = 222) of follow-up. Using linear mixed-effects models, we investigated associations of LGCS with progression of brain atrophy, WMH, and cognitive decline. LGCS was associated with greater progression of global brain atrophy (estimate -0.03; 95%CI, -0.06 to -0.01; p = 0.002), and a greater decline in executive functioning (estimate -0.02; 95%CI, -0.031 to -0.01; p < 0.001) and memory (estimate -0.012; 95%CI, -0.02 to -0.001; p = 0.032), independent of demographics, cardiovascular risk factors, and incident brain infarcts on MRI. No association was observed between LGCS and progression of WMH. Our results indicate that LGCS may represent an early marker of greater future brain atrophy and cognitive decline.

White matter hyperintensity shape is associated with cognitive functioning - the SMART-MR study.

White matter hyperintensity (WMH) shape has been associated with the severity of the underlying brain pathology, suggesting it is a potential neuroimaging marker of WMH impact on brain function. In 563 patients with vascular disease (58 ± 10 years), we examined the relationship between WMH volume, shape, and cognitive functioning. WMH volume and shape were automatically determined on 1.5T brain MRI data. Standardized linear regression analyses estimated the association between WMH volume and shape (concavity index, solidity, convexity, fractal dimension, and eccentricity) and memory and executive functioning, adjusted for age, sex, educational level, and reading ability. Larger WMH volumes were associated with lower executive functioning Z-scores (b (95%-CI): -0.09 (-0.17;-0.01)). Increased shape complexity of periventricular/confluent WMH associated with lower executive functioning (concavity index +1SD: -0.13 (-0.20;-0.06); solidity -1SD: -0.09 (-0.17;-0.02)) and lower memory function (fractal dimension +1SD: -0.10 (-0.18;-0.02)). Of note, the association between concavity index and executive functioning was independent of WMH volume (-0.12 (-0.19;-0.04)). Our results suggest that WMH shape contains additional information about WMH burden, not otherwise captured by WMH volume.

The role of cognitive and brain reserve in memory decline and atrophy rate in mid and late-life: The SMART-MR study.

OBJECTIVE: Investigate associations of cognitive and brain reserve with trajectories of memory decline in mid-life and late-life, and whether the relationship of memory decline with atrophy differs as a function of reserve. METHODS: Participants were 989 Dutch middle-aged to older adults from the SMART-MR prospective cohort, followed up to 12 years with up to 3 measurements of memory and brain MRI. Education and Dutch National Adult Reading Test (DART) were used as proxies of cognitive reserve, and intracranial volume (ICV) and baseline brain parenchymal fraction (BPF) for brain reserve. Univariate growth curve models analyzed associations of reserve with memory decline, and multiple-group bivariate growth curve models tested the longitudinal brain-memory relationship as a function of reserve. Models were additionally stratified by mid-life and late-life. RESULTS: Higher DART, education, and BPF were related to a slower rate of memory decline, particularly in late-life, but ICV was not. A positive covariance indicated that an individual who undergoes atrophy also undergoes memory decline-this relationship did not differ across cognitive or brain reserve, but was not present in mid-life. Memory declined slower than brain volume, yet rates were more similar in the low DART, education, and BPF groups. DISCUSSION: Higher cognitive (DART, education) and brain reserve (BPF) work protectively in longitudinal memory change. ICV is an inappropriate proxy of brain reserve, failing to show any association with memory performance at baseline or over time. Deconstructing relationships of reserve capacities with longitudinal cognitive and brain outcomes may identify focus areas with potential for intervention.

Cortical cerebral microinfarcts on 7T MRI: Risk factors, neuroimaging correlates and cognitive functioning - The Medea-7T study.

We determined the occurrence and association of cortical cerebral microinfarcts (CMIs) at 7 T MRI with risk factors, neuroimaging markers of small and large vessel disease, and cognitive functioning. Within the Medea-7T study, a diverse cohort of older persons with normal cognition, patients with vascular disease, and memory clinic patients, we included 386 participants (68 ± 9 years) with available 7 T and 1.5 T/3T brain MRI, and risk factor and neuropsychological data. CMIs were found in 10% of participants and were associated with older age (RR = 1.79 per +10 years, 95%CI 1.28-2.50), history of stroke or TIA (RR = 4.03, 95%CI 2.18-7.43), cortical infarcts (RR = 5.28, 95%CI 2.91-9.55), lacunes (RR = 5.66, 95%CI 2.85-11.27), cerebellar infarcts (RR = 2.73, 95%CI 1.27-5.84) and decreased cerebral blood flow (RR = 1.35 per -100 ml/min, 95%CI 1.00-1.83), after adjustment for age and sex. Furthermore, participants with >2 CMIs had 0.5 SD (95%CI 0.05-0.91) lower global cognitive performance, compared to participants without CMIs. Our results indicate that CMIs on 7 T MRI are observed in vascular and memory clinic patients with similar frequency, and are associated with older age, history of stroke or TIA, other brain infarcts, and poorer global cognitive functioning.

Reduced parenchymal cerebral blood flow is associated with greater progression of brain atrophy: The SMART-MR study.

Global cerebral hypoperfusion may be involved in the aetiology of brain atrophy; however, long-term longitudinal studies on this relationship are lacking. We examined whether reduced cerebral blood flow was associated with greater progression of brain atrophy. Data of 1165 patients (61 ± 10 years) from the SMART-MR study, a prospective cohort study of patients with arterial disease, were used of whom 689 participated after 4 years and 297 again after 12 years. Attrition was substantial. Total brain volume and total cerebral blood flow were obtained from magnetic resonance imaging scans and expressed as brain parenchymal fraction (BPF) and parenchymal cerebral blood flow (pCBF). Mean decrease in BPF per year was 0.22% total intracranial volume (95% CI: -0.23 to -0.21). Mean decrease in pCBF per year was 0.24 ml/min per 100 ml brain volume (95% CI: -0.29 to -0.20). Using linear mixed models, lower pCBF at baseline was associated with a greater decrease in BPF over time (p = 0.01). Lower baseline BPF, however, was not associated with a greater decrease in pCBF (p = 0.43). These findings indicate that reduced cerebral blood flow is associated with greater progression of brain atrophy and provide further support for a role of cerebral blood flow in the process of neurodegeneration.

Intracranial vessel wall lesions on 7T MRI and MRI features of cerebral small vessel disease: The SMART-MR study.

The etiology of cerebral small vessel disease (CSVD) is the subject of ongoing research. Although intracranial atherosclerosis (ICAS) has been proposed as a possible cause, studies on their relationship remain sparse. We used 7 T vessel wall magnetic resonance imaging (MRI) to study the association between intracranial vessel wall lesions-a neuroimaging marker of ICAS-and MRI features of CSVD. Within the SMART-MR study, cross-sectional analyses were performed in 130 patients (68 ± 9 years; 88% male). ICAS burden-defined as the number of vessel wall lesions-was determined on 7 T vessel wall MRI. CSVD features were determined on 1.5 T and 7 T MRI. Associations between ICAS burden and CSVD features were estimated with linear or modified Poisson regression, adjusted for age, sex, vascular risk factors, and medication use. In 125 patients, ≥1 vessel wall lesions were found (mean 8.5 ± 5.7 lesions). ICAS burden (per + 1 SD) was associated with presence of large subcortical and/or cortical infarcts (RR = 1.65; 95%CI: 1.12-2.43), lacunes (RR = 1.45; 95% CI: 1.14-1.86), cortical microinfarcts (RR = 1.48; 95%CI: 1.13-1.94), and total white matter hyperintensity volume (b = 0.24; 95%CI: 0.02-0.46). Concluding, patients with a higher ICAS burden had more CSVD features, although no evidence of co-location was observed. Further longitudinal studies are required to determine if ICAS precedes development of CSVD.

Vascular Risk Factors of Hippocampal Subfield Volumes in Persons without Dementia: The Medea 7T Study.

BACKGROUND: Vascular risk factors have been associated with risk of Alzheimer's disease (AD) and volume loss of the hippocampus, but the associations with subfields of the hippocampus are understudied. Knowing if vascular risk factors contribute to hippocampal subfield atrophy may improve our understanding of vascular contributions to neurodegenerative diseases. OBJECTIVE: To investigate the associations between age, sex, and vascular risk factors with hippocampal subfields volumes on 7T MRI in older persons without dementia. METHODS: From the Medea 7T study, 283 participants (67±9 years, 68% men) without dementia had 7T brain MRI and hippocampal subfield segmentation. Subfields were automatically segmented on the 3D T2-weighted 7T images with ASHS software. Using linear mixed models, we estimated adjusted associations of age, sex, and vascular risk factors with z-scores of volumes of the entorhinal cortex (ERC), subiculum (SUB), Cornu Ammonis (CA)1, CA2, CA3, CA4, and dentate gyrus (DG), and tail as multivariate correlated outcomes. RESULTS: Increasing age was associated with smaller volumes in all subfields, except CA4/DG. Current smoking was associated with smaller ERC and SUB volumes; moderate alcohol use with smaller CA1 and CA4/DG, obesity with smaller volumes of ERC, SUB, CA2, CA3, and tail; and diabetes mellitus with smaller SUB volume. Sex, former smoking, and hypertension were not associated with subfield volumes. When formally tested, no risk factor affected the subfield volumes differentially. CONCLUSION: Several vascular risk factors were associated with smaller volumes of specific hippocampal subfields. However, no statistical evidence was found that subfields were differentially affected by these risk factors.

Intracranial atherosclerosis on 7T MRI and cognitive functioning: The SMART-MR study.

OBJECTIVE: To investigate the association between intracranial atherosclerosis (ICAS) and cognitive functioning in patients with a history of vascular disease. METHODS: Within the Second Manifestations of Arterial Disease-Magnetic Resonance (SMART-MR) study, cross-sectional analyses were performed in 130 patients (mean ± SD age 68 ± 9 years) with 7T vessel wall MRI data. Vessel wall lesions were rated according to established criteria and summed into a circulatory and artery-specific ICAS burden. Associations between ICAS burden and Z scores of memory, executive functioning, working memory, and processing speed were estimated using linear regression analyses adjusted for age, sex, education, reading ability, and vascular risk factors. RESULTS: A total of 125 patients (96%) had ≥1 vessel wall lesion; the mean ICAS burden was 8.5 ± 5.7. A statistically nonsignificant association was found between total ICAS burden and memory (b = -0.03 per +1 lesion; 95% confidence interval [CI] -0.05 to 0.00). No associations were found for the other domains. A statistically significant association was found for ICAS burden of the posterior cerebral artery (PCA) and memory (b = -0.12 per +1 lesion; 95% CI -0.23 to -0.01) and executive functioning (b = -0.10 per +1 lesion; 95% CI -0.19 to -0.01). Statistically nonsignificant associations were found for the anterior cerebral artery (ACA) burden and memory (b = -0.13 per +1 lesion; 95% CI -0.26 to 0.01) and executive functioning (b = -0.11 per +1 lesion; 95% CI -0.22 to 0.01). Additional adjustments for large infarcts, white matter hyperintensities, lacunes, and ≥50% carotid stenosis produced similar results. CONCLUSIONS: Our results suggest an artery-specific vulnerability of memory and executive functioning to ICAS, possibly due to strategic brain regions involved with these cognitive domains, which are located in the arterial territory of the PCA and ACA.

Subjective cognitive decline, brain imaging biomarkers, and cognitive functioning in patients with a history of vascular disease: the SMART-Medea study.

We estimated associations of subjective cognitive decline (SCD) with neuroimaging markers of dementia and cognitive functioning in patients with a history of vascular disease without objective cognitive impairment. Within the Second Manifestations of ARTerial disease-Memory, depression and aging study, 599 patients (62 ± 9 years) had 1.5 T brain magnetic resonance imaging and cognitive testing at the baseline and after 8 years of follow-up. Using multiple regression analyses, we estimated cross-sectional and longitudinal associations of SCD according to research criteria with volumes of total brain, hippocampus, white matter hyperintensities, and presence of lacunes and with memory, executive functioning, information processing speed, and working memory. SCD was associated with increased risk of lacunes at the baseline (relative risk = 1.48, 95% confidence interval: 1.03; 2.12) but not during follow-up. No significant associations with volumes of white matter hyperintensities, total brain, or hippocampus were observed. SCD was cross-sectionally associated with poorer executive functioning and speed but not during follow-up. More prospective studies are needed to further elucidate the relationship between SCD, brain imaging markers, and cognitive decline and the role of SCD in the preclinical stage of Alzheimer's disease.

The association between lacunes and white matter hyperintensity features on MRI: The SMART-MR study.

Lacunes and white matter hyperintensities (WMHs) are features of cerebral small vessel disease (CSVD) that are associated with poor functional outcomes. However, how the two are related remains unclear. In this study, we examined the association between lacunes and several WMH features in patients with a history of vascular disease. A total of 999 patients (mean age 59 ± 10 years) with a 1.5 T brain magnetic resonance imaging (MRI) scan were included from the SMART-MR study. Lacunes were scored visually and WMH features (volume, subtype and shape) were automatically determined. Analyses consisted of linear and Poisson regression adjusted for age, sex, and total intracranial volume (ICV). Patients with lacunes (n = 188; 19%) had greater total (B = 1.03, 95% CI: 0.86 to 1.21), periventricular/confluent (B = 1.08, 95% CI: 0.89 to 1.27), and deep (B = 0.71, 95% CI: 0.44 to 0.97) natural log-transformed WMH volumes than patients without lacunes. Patients with lacunes had an increased risk of confluent type WMHs (RR = 2.41, 95% CI: 1.98 to 2.92) and deep WMHs (RR = 1.41, 95% CI: 1.22 to 1.62) and had a more irregular shape of confluent WMHs than patients without lacunes, independent of total WMH volume. In conclusion, we found that lacunes on MRI were associated with WMH features that correspond to more severe small vessel changes, mortality, and poor functional outcomes.

Hippocampal sulcal cavities: prevalence, risk factors and association with cognitive performance. The SMART-Medea study and PREDICT-MR study.

Hippocampal sulcal cavities (HSCs) are frequently observed on MRI, but their etiology and relevance is unclear. HSCs may be anatomical variations, or result from pathology. We assessed the presence of HSCs, and their cross-sectional association with demographics, vascular risk factors and cognitive functioning in two study samples. Within a random sample of 92 patients with vascular disease from the SMART-Medea study (mean age = 62, SD = 9 years) and 83 primary care patients from the PREDICT-MR study (mean age = 62, SD = 12 years) one rater manually scored HSCs at 1.5 T 3D T1-weighted coronal images blind to patient information. We estimated relative risks of age, sex and vascular risk factors with presence of HSCs using Poisson regression with log-link function and robust standard errors adjusted for age and sex. Using ANCOVA adjusted for age, sex, and education we estimated the association of the number of HSCs with memory, executive functioning, speed, and working memory. In the SMART-Medea study HSCs were present in 65% and in 52% in the PREDICT-MR study (χ2 = 2.99, df = 1, p = 0.08). In both samples, no significant associations were observed between presence of HSCs and age (SMART-Medea: RR = 1.00; 95%CI 0.98-1.01; PREDICT-MR: RR = 1.01; 95%CI 0.99-1.03), sex, or vascular risk factors. Also, no associations between HSCs and cognitive functioning were found in either sample. HSCs are frequently observed on 1.5 T MRI. Our findings suggest that, in patients with a history of vascular disease and primary care attendees, HSCs are part of normal anatomic variation of the human hippocampus rather than markers of pathology.

Intracranial Vessel Wall Lesions on 7T MRI (Magnetic Resonance Imaging).

Background and Purpose- Intracranial vessel wall lesions are a novel imaging marker of intracranial atherosclerosis (ICAS), but data on their occurrence and risk factors are lacking. Our aim was to study the frequency, distribution, and risk factors of intracranial vessel wall lesions on 7T magnetic resonance imaging in patients with a history of vascular disease. Methods- Within the SMART-MR study (Second Manifestations of Arterial Disease-Magnetic Resonance), cross-sectional analyses were performed in 130 patients (68±9 years) with assessable 7T intracranial vessel wall-magnetic resonance imaging data. Associations between vascular risk factors and ICAS burden, defined as the total number of vessel wall lesions, were estimated using linear regression analyses with ICAS burden as the dependent variable, adjusted for age and sex. Results- Ninety-six percent of patients had ≥1 vessel wall lesion. The mean±SD (range) ICAS burden was 8.5±5.7 (0-32) lesions. Significant associations were found between ICAS burden and age ( b=2.0 per +10 years; 95% CI, 0.81- 3.10), systolic blood pressure ( b=0.9 per +10 mm Hg; 95% CI, 0.27-1.42), diabetes mellitus ( b=3.2 for presence of diabetes mellitus; 95% CI, 0.79-5.72), hemoglobin A1c level ( b=1.2 per +1%; 95% CI, 0.19-2.26), apoB (apolipoprotein-B) ( b=4.7 per +1 g/L; 95% CI, 0.07-9.35), and hs-CRP (high-sensitivity C-reactive protein) level ( b=2.7 for hs-CRP >3 mg/L; 95% CI, 0.22-5.11). No significant associations were found with sex, smoking, and other lipid-factors. Conclusions- Vessel wall lesions are a novel and direct magnetic resonance imaging marker of ICAS. In this cohort, 96% of patients had at least 1 lesion on 7T vessel wall-magnetic resonance imaging. More lesions were found with older age, higher systolic blood pressure, diabetes mellitus, and higher levels of hemoglobin A1c, apoB, and hs-CRP.

Detection and characterization of small infarcts in the caudate nucleus on 7 Tesla MRI: The SMART-MR study.

Small infarcts are among the key imaging features of cerebral small vessel disease (CSVD), but remain largely undetected on conventional MRI. We aimed to evaluate (1) imaging criteria for the detection of small infarcts in the caudate nucleus on 7T MRI, (2) intra- and inter-rater agreement, (3) frequency and (4) detection rate on 7T versus 1.5T MRI. In 90 patients (68 ± 8 years) with a history of vascular disease from the SMART-MR study, we defined 7T imaging criteria for cavitated and non-cavitated small infarcts in the caudate nucleus. In a separate set of 23 patients from the SMART study, intra-rater and inter-rater agreement was excellent for presence, number, and individual locations (Kappa's, ICCs, and Dice similarity coefficients ranged from 0.85 to 1.00). In the 90 patients, 21 infarcts (20 cavitated) in 12 patients were detected on 7T (13%) compared to 7 infarcts in 6 patients on 1.5T (7%). In conclusion, we established reproducible imaging criteria for the detection of small infarcts in the caudate nucleus on 7T MRI and showed that 7T MRI allows for a higher detection rate than conventional 1.5T MRI. These imaging criteria can be used in future studies to provide new insights into the pathophysiology of CSVD.

Clinical vascular imaging in the brain at 7T.

Stroke and related cerebrovascular diseases are a major cause of mortality and disability. Even at standard-field-strengths (1.5T), MRI is by far the most sensitive imaging technique to detect acute brain infarctions and to characterize incidental cerebrovascular lesions, such as white matter hyperintensities, lacunes and microbleeds. Arterial time-of-flight (TOF) MR angiography (MRA) can depict luminal narrowing or occlusion of the major brain feeding arteries, and this without the need for contrast administration. Compared to 1.5T MRA, the use of high-field strength (3T) and even more so ultra-high-field strengths (7T), enables the visualization of the lumen of much smaller intracranial vessels, while adding a contrast agent to TOF MRA at 7T may enable the visualization of even more distal arteries in addition to veins and venules. Moreover, with 3T and 7T, the arterial vessel walls beyond the circle of Willis become visible with high-resolution vessel wall imaging. In addition, with 7T MRI, the brain parenchyma can now be visualized on a submillimeter scale. As a result, high-resolution imaging studies of the brain and its blood supply at 7T have generated new concepts of different cerebrovascular diseases. In the current article, we will discuss emerging clinical applications and future directions of vascular imaging in the brain at 7T MRI.

Appendicitis Presenting As Cellulitis of the Right Leg.

BACKGROUND: Several infectious processes of intra-abdominal origin may atypically present as skin or soft tissue infections or abscess in the thigh. CASE REPORT: We describe the case of a 73-year-old woman who presented to the emergency department with the clinical picture of a skin infection of the right leg. The patient's condition deteriorated during medical treatment with intravenous antibiotics. Subsequent radiologic imaging revealed that the complaints were caused by a bulging retroperitoneal appendicular abscess along the iliopsoas muscle, although the patient experienced no abdominal symptoms. The patient recovered completely after surgical intervention. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Timely performance of anatomic imaging in patients with unexplained skin or soft tissue infections and thigh abscesses is important because these findings may be manifestations of an abdominal pathology. A correct diagnosis in the emergency department prohibits delays in treatment.

Identification of hypertrophy- and heart failure-associated genes by combining in vitro and in vivo models.

Heart failure (HF) is a complex disease involving multiple changes including cardiomyocyte hypertrophy (growth). Here we performed a set of screens in different HF and hypertrophy models to identify differentially expressed genes associated with HF and/or hypertrophy. Hypertensive Ren2 rats and animals with postmyocardial infarction (post-MI) HF were used as in vivo HF models, and neonatal rat cardiomyocytes treated with hypertrophy inducing hormones phenylephrine, endothelin-1, and isoproterenol were used as in vitro models. This combined approach revealed a robust set of genes that were differentially expressed both in vitro and in vivo. This included known genes like NPPA (ANP) and FHL1, but also novel genes not previously associated with hypertrophy/HF. Among these are PTGIS, AKIP1, and Dhrs7c, which could constitute interesting targets for further investigations. We also identified a number of in vivo specific genes and these appeared to be enriched for fibrosis, wounding, and stress responses. Therefore a number of novel genes within this in vivo specific list could be related to fibroblasts or other noncardiomyocytes present in the heart. We also observed strong differences between the two HF rat models. For example KCNE1 was strongly upregulated in Ren2, but not in post-MI HF rats, suggesting possible etiology-specific differences. Moreover, Gene Ontology analysis revealed that genes involved in fatty acid oxidation were specifically down regulated in the post-MI group only. Together these results show that combining multiple models, both in vivo and in vitro, can provide a robust set of hypertrophy/HF-associated genes. Moreover it provides insight in the differences between the different etiology models and neurohormonal effects.