Annelies W. E. Weverling-Rijnsburger

Magnetization transfer imaging in normal aging, mild cognitive impairment, and Alzheimer's disease.

The purpose of this study was to assess whether structural brain damage as detected by volumetric magnetization transfer imaging (MTI) is present in mild cognitive impairment (MCI) and Alzheimers disease (AD) and, if so, whether these abnormalities are global in character or restricted to the temporal lobe. Volumetric MTI analysis of the whole brain and temporal and frontal lobes was performed in 25 patients with probable AD, in 13 patients with MCI, and in 28 controls. Magnetization transfer ratio (MTR) histograms were produced, from which we derived measures for structural brain damage and atrophy. The peak heights of the MTR histograms of MCI and AD patients were lower than those of controls for the whole brain and temporal and frontal lobes, reflecting structural brain damage. AD patients had more atrophy than controls in all regions that were studied. MCI patients differed from controls for temporal lobe atrophy only. Volumetric MTI demonstrates structural changes that are related to cognitive decline in large parts of the brain of AD patients. Moreover, structural changes also were observed in MCI patients, indicating that widespread brain damage can be demonstrated before patients are clinically demented.

Memory complaints in patients with normal cognition are associated with smaller hippocampal volumes.

Abstract.We aimed to investigate volumetry of the medial temporal lobe in patients with subjective memory complaints without any cognitive impairment. This study included 20 patients with subjective memory complaints and normal cognitive function and 28 controls without memory complaints. Volumes of the hippocampus and parahippocampal gyrus (PHG) were measured using coronal T1-weighted MR images. Cognitive functions were assessed using the Cambridge Cognitive Examination. Depressive symptoms were assessed using the Geriatric Depression Scale. Differences between groups were analysed using t-tests. Patients with subjective memory complaints had a higher education and more depressive symptoms than controls (p < 0.01). Moreover, they had smaller left hippocampal volumes than controls (p < 0.01). There were no differences between groups in the volume of the right hippocampus or PHG. There was a moderate association between the volume of left hippocampus and left PHG and memory-score (r = 0.32, p = 0.03; r = 0.34, p = 0.02). We concluded that memory complaints in patients without any cognitive impairment were associated with smaller left hippocampal volumes and more depressive symptoms. These preliminary results suggest that memory complaints may reflect minimal brain deficits associated with impending dementia, depression or a combination of both disorders.

Not Acute but Chronic Hypertriglyceridemia Is Associated With Impaired Endothelium-Dependent Vasodilation: Reversal After Lipid-Lowering Therapy by Atorvastatin

There is controversy regarding the relation between hypertriglyceridemia (HTG) and endothelial function. This study was designed to investigate endothelial function in a patient group with chronic HTG, before and during lipid-lowering therapy by atorvastatin. In addition, the effects of acute HTG on endothelial function were studied in normolipidemic individuals. Eight male patients with chronic HTG were studied before and after 6 weeks of lipid-lowering treatment with 80 mg atorvastatin once daily. Ten age-matched control subjects were studied at baseline and immediately after a high-dose infusion of artificial triglycerides. The endothelium-dependent response to serotonin was attenuated in the HTG group, whereas the response to acetylcholine was comparable to the response in the control group. The response to the endothelium-independent vasodilator nitroprusside was comparable in both groups. In response to atorvastatin therapy, serum triglyceride and cholesterol levels decreased significantly by 43% (paired t test, P=0.017) and 38% (paired t test, P=0.012), respectively. After 6 weeks of treatment, the forearm blood flow response to serotonin improved from 63% to 106% (ANOVA, P<0.001). Induction of acute HTG in the control subjects did not affect the forearm blood flow responses to serotonin and nitroprusside; however, the response to acetylcholine was paradoxically increased. In conclusion, patients with chronic HTG have an impaired endothelium-dependent vasodilation to serotonin that is normalized after 6 weeks of lipid-lowering therapy by atorvastatin.

Patients with Alzheimer's disease display a pro-inflammatory phenotype

BACKGROUND Inflammation plays a pivotal role in amyloid plaque progression thereby contributing to Alzheimers disease-related neurodegeneration. We hypothesized that patients with Alzheimers disease have an innate pro-inflammatory phenotype, as compared to control subjects without dementia. METHODS Patients with a diagnosis of probable Alzheimers disease (n=12) and control subjects without signs of dementia (n=18) were enrolled. Whole blood samples were stimulated ex vivo with endotoxin under standard conditions. Cytokine levels were assessed by ELISA and compared by Mann-Whitneyll-test after log transformation. RESULTS Patients with Alzheimers disease had seven- to ten-fold higher IL-1beta production relative to the amount of IL-10 both at the low (p=0.006) and high concentration of endotoxin (p=0.007). Subjects who display a pro-inflammatory phenotype as defined by a high IL-1beta/IL-10 ratio had 13.0-fold higher odds (95% CI: 2.1-82) to have dementia. CONCLUSION The data support the hypothesis that a pro-inflammatory phenotype contributes to the development of Alzheimers disease.

Interaction of medial temporal lobe atrophy and white matter hyperintensities in AD

The authors investigated the interaction between medial temporal lobe (MTL) atrophy and white matter hyperintensities (WMH) in Alzheimer disease (AD). They measured the MTL and WMH on MRI in 58 AD patients and 28 controls. MTL atrophy was associated with an increased risk of AD (OR = 6.2), but there was no significant association between WMH and AD. Moreover, there was an interaction between MTL and WMH (p = 0.045). These results suggest that vascular and Alzheimer-type pathology act in synergy in the clinical syndrome of AD.

Cognitive decline in AD and mild cognitive impairment is associated with global brain damage.

ObjectiveTo investigate the relationships between structural damage in the whole brain, the temporal lobes, and the frontal lobes and cognitive decline at old age. The authors hypothesized that widespread brain damage as quantified using magnetization transfer imaging (MTI) is related to global cognitive decline, whereas regional damage to the temporal lobes is related to memory impairment, and regional damage to the frontal lobes is related to executive dysfunctioning. Methods Cognitive function of 22 patients with probable AD, 13 patients with mild cognitive impairment (MCI), and 28 elderly controls was assessed using an extensive neuropsychological test battery. Structural damage in the whole brain, the temporal lobes, and the frontal lobes was estimated using volumetric MTI analysis. Associations between MTI measures and neuropsychological tests were investigated using Pearson correlation analysis. Results MTI measures of the whole brain, as well as the temporal and the frontal lobes, were strongly associated with global cognitive deterioration and impairment in memory, orientation, language, praxis, gnosis, and executive functioning. However, there were no specific cognitive correlates of regional brain damage to the temporal and frontal lobes. Conclusions Using whole brain volumetric magnetization transfer imaging, the authors demonstrated that cognitive decline in patients with mild cognitive impairment and AD is associated with widespread structural brain damage. As there were no specific relationships between regional brain damage and impairment of specific cognitive functions, pathology in AD and mild cognitive impairment is much more generalized than was expected.

Magnetization transfer imaging of gray and white matter in mild cognitive impairment and Alzheimer's disease

OBJECTIVE To assess whether structural brain damage as detected by magnetization transfer imaging (MTI) in Alzheimers disease (AD) and mild cognitive impairment (MCI) is located in the gray matter (GM) and/or the white matter (WM). METHODS Fifty-five AD patients, 19 MCI patients and 43 subjects with normal cognitive function participated in this study. GM and WM segmentations were generated from dual fast spin-echo MR images. These masks were co-registrated to MT images for volumetric MTI-analysis of the GM and WM. RESULTS AD patients had a lower GM volume than controls. Both MCI and AD patients had more structural brain damage in both GM and WM than subjects with normal cognition. Cerebral lesion load in both GM and WM was associated with the degree of cognitive impairment. CONCLUSION Using MTI, structural brain changes that are related to cognitive impairment could be demonstrated in both GM and WM of patients with AD and MCI. These results suggest that cerebral changes are present in GM and WM even before patients are clinically demented.

Neuropsychological correlates of MRI measures in the continuum of cognitive decline at old age

Objective: To investigate the independent associations between medial temporal lobe atrophy and white matter hyperintensities (WMH) and cognitive functions in the elderly. Methods: Cognitive functions of 41 Alzheimer’s disease patients, 20 patients with mild cognitive impairment and 28 elderly subjects without memory complaints were assessed using a neuropsychological test battery. Quantitative MRI measures of medial temporal lobe volume and WMH were obtained. Multiple regression analyses were performed to assess the independent contribution of MRI measures to impairment in several cognitive functions. Results: Scores on the Wechsler Memory Scale and Trails B depended selectively on medial temporal lobe volume, whereas WMH selectively contributed to performance on Trails A. Medial temporal lobe volume and WMH both contributed to scores on the Cambridge Cognitive Examination and the Boston naming task. Conclusions: MRI measures suggestive of Alzheimer-type pathology and microvascular pathology independently contribute to cognitive decline at old age. Memory impairment as measured using the Wechsler Memory Scale and performance on Trails B primarily depended on medial temporal lobe atrophy. Psychomotor slowness, as measured using Trails A, mainly depended on WMH. These results suggest that vascular pathology and Alzheimer-type pathology each have specific cognitive correlates.

Lobar Distribution of Changes in Gray Matter and White Matter in Memory Clinic Patients : Detected Using Magnetization Transfer Imaging

BACKGROUND AND PURPOSE: Previous studies have shown involvement of both gray matter (GM) and white matter (WM) in mild cognitive impairment (MCI) and Alzheimer disease (AD). In this study, we assessed the lobar distribution of the GM and WM pathology over the brain and the association of lobar distribution with global cognitive decline. MATERIALS AND METHODS: Fifty-five patients with AD, 19 patients with MCI, and 43 subjects with normal cognitive function participated in this study. GM and WM were segmented on dual fast spin-echo and fluid-attenuated inversion recovery MR images. A custom template representing anatomic areas was applied. Magnetization transfer imaging (MTI) peak height and mean magnetization transfer ratio (MTR) provided measures for structural brain damage. RESULTS: Both mean MTR and MTI peak height showed that patients with AD had more structural brain damage in the GM of all lobes compared with controls. Patients with MCI had lower GM peak height compared with controls for the temporal and frontal lobe. WM peak height was lower for all lobes investigated for patients with both AD and MCI. WM mean MTR was lower in the frontal, parietal, and temporal lobes for patients with AD compared with controls. Age and both temporal GM peak height and mean MTR were the only parameters that predicted cognition. CONCLUSION: This study shows that in addition to more focal GM MTI changes in the temporal and frontal lobes, widespread WM changes are present in the earliest stages of AD. This might point to an important role for WM pathology in the earliest stage of AD.

Optimal screening for increased risk for adverse outcomes in hospitalised older adults

Background: screening for frailty might help to prevent adverse outcomes in hospitalised older adults. Objective: to identify the most predictive and efficient screening tool for frailty. Design and setting: two consecutive observational prospective cohorts in four hospitals in the Netherlands. Subjects: patients aged ≥70 years, electively or acutely hospitalised for ≥2 days. Methods: screening instruments included in the Dutch Safety Management Programme [VeiligheidsManagementSysteem (VMS)] on four geriatric domains (ADL, falls, undernutrition and delirium) were used and the Identification of Seniors At Risk, the 6-item Cognitive Impairment Test and the Mini-Mental State Examination were assessed. Three months later, adverse outcomes including functional decline, high-healthcare demand or death were determined. Correlation and regression tree analyses were performed and predictive capacities were assessed. Results: follow-up data were available of 883 patients. All screening instruments were similarly predictive for adverse outcome (predictive power 0.58–0.66), but the percentage of positively screened patients (13–72%), sensitivity (24–89%) and specificity (35–91%) highly differed. The strongest predictive model for frailty was scoring positive on ≥3 VMS domains if aged 70–80 years; or being aged ≥80 years and scoring positive on ≥1 VMS domains. This tool classified 34% of the patients as frail with a sensitivity of 68% and a specificity of 74%. Comparable results were found in the validation cohort. Conclusions: the VMS-tool plus age (VMS+) offers an efficient instrument to identify frail hospitalised older adults at risk for adverse outcome. In clinical practice, it is important to weigh costs and benefits of screening given the rather low-predictive power of screening instruments.