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Biomedical subjects

Reinhold Schmidt

Publications and source records attributed to Reinhold Schmidt.

At least 19 recordsLinked to original sources
PubMed2006

C-reactive protein, carotid atherosclerosis, and cerebral small-vessel disease: results of the Austrian Stroke Prevention Study.

BACKGROUND AND PURPOSE: C-reactive protein (CRP) is an inflammatory marker known to be a risk factor for stroke. We examined the associations between CRP, carotid atherosclerosis, white matter lesions, and lacunes as manifestations of cerebral large- and small-vessel disease. METHODS: In the community-based Austrian Stroke Prevention Study, CRP concentrations were measured by a highly sensitive assay in 700 participants at baseline. All underwent carotid duplex scanning, and a subset of 505 subjects underwent brain magnetic resonance imaging. Imaging was repeated after 3 and 6 years. We graded carotid atherosclerosis in both common and internal carotid arteries on a 5-point scale and calculated the sum of scores as an index of the severity of carotid atherosclerosis. The volume of white matter lesions and the number of lacunes were considered small vessel disease-related brain abnormalities. RESULTS: After adjustment for vascular risk factors, the severity and progression of extracranial carotid atherosclerosis increased with increasing quintiles of CRP. Only study participants in the fourth and fifth quintile (>2.50 mg/L) had significantly more baseline atherosclerosis and greater progression when we used the first quintile (<0.80 mg/L) as a reference. No interactions were seen between CRP quintiles and vascular risk factors for carotid atherosclerosis. The associations between severity and progression of small vessel disease-related brain abnormalities and CRP were nonsignificant. CONCLUSIONS: We found evidence for differential effects of CRP in different beds of the arterial brain supply. CRP was a marker for active carotid atherosclerosis but not for small vessel disease-related brain lesions.

Aged↗
PubMed2006

Corpus callosum atrophy is associated with mental slowing and executive deficits in subjects with age-related white matter hyperintensities: the LADIS Study.

BACKGROUND: Previous research has indicated that corpus callosum atrophy is associated with global cognitive decline in neurodegenerative diseases, but few studies have investigated specific cognitive functions. OBJECTIVE: To investigate the role of regional corpus callosum atrophy in mental speed, attention and executive functions in subjects with age-related white matter hyperintensities (WMH). METHODS: In the Leukoaraiosis and Disability Study, 567 subjects with age-related WMH were examined with a detailed neuropsychological assessment and quantitative magnetic resonance imaging. The relationships of the total corpus callosum area and its subregions with cognitive performance were analysed using multiple linear regression, controlling for volume of WMH and other confounding factors. RESULTS: Atrophy of the total corpus callosum area was associated with poor performance in tests assessing speed of mental processing--namely, trail making A and Stroop test parts I and II. Anterior, but not posterior, corpus callosum atrophy was associated with deficits of attention and executive functions as reflected by the symbol digit modalities and digit cancellation tests, as well as by the subtraction scores in the trail making and Stroop tests. Furthermore, semantic verbal fluency was related to the total corpus callosum area and the isthmus subregion. CONCLUSIONS: Corpus callosum atrophy seems to contribute to cognitive decline independently of age, education, coexisting WMH and stroke. Anterior corpus callosum atrophy is related to the frontal-lobe-mediated executive functions and attention, whereas overall corpus callosum atrophy is associated with the slowing of processing speed.

Aged↗
PubMed2006

Liver carboxylesterase cleaves surfactant protein (SP-) B and promotes surfactant subtype conversion.

Conversion of the biophysically active large surfactant aggregate subtype of alveolar surfactant into the less surface active small surfactant aggregates occurs in vitro and in vivo, possibly in dependency of a carboxylesterase, entitled surfactant convertase. The substrate has yet not been safely identified. Utilizing the in vitro cycling assay we investigated conversion of an organic rabbit lavage extract reconstituted with SP-A. Porcine liver carboxylesterase, which is closely related to surfactant convertase, induced subtype conversion to a similar degree as compared with native lavage fluid containing endogenous convertase. In addition, we asked for cleavage products of SP-B and identified a approximately 12 kDa band upon cycling with liver carboxylesterase, having the same N-terminus as mature SP-B. A band of same molecular weight was found in native lavage fluid after in vitro conversion mediated by the endogenous convertase. We conclude that SP-B plays a pivotal role during subtype conversion and represents the substrate for surfactant convertase.

Amino Acid Sequence↗
PubMed2006

The impact of our genes: consequences of the apolipoprotein E polymorphism in Alzheimer disease and multiple sclerosis.

Epidemiological studies provide strong evidence that susceptibility to multiple sclerosis (MS) is in part genetically determined. Likewise the heterogeneity in clinical manifestations, temporal course, severity, and in the pathological processes of MS are probably also influenced by our genes. Apolipoprotein E (apoE) polymorphism has been considered a candidate for impacting on MS because of its numerous functions related to brain tissue and evidence for an association with a variety of cerebral disorders, specifically Alzheimer's disease (AD). The apoE alleles epsilon2, epsilon3, and epsilon4 are known to impact differently on aspects such as neuronal growth and repair, neuroprotection and inflammation. After a review of the strong association of the apoE polymorphism with AD, we review the results on MS. These are far less homogenous but have gained support from morphologic and metabolic measures obtained with magnetic resonance imaging indicating a greater extent of brain destruction with the apoE epsilon4 allele. Evidence for a protective role of the epsilon2 allele in MS is weak. In view of the association with AD it is tempting to speculate that neuropsychologic functioning in MS might be even more strongly related to the apoE polymorphism and especially to the epsilon4 allele than other deficits, but few data on this issue are yet available. While part of the association of the apoE polymorphism with AD is supposed to be caused by apoE-isoform dependent effects on amyloid-beta deposition, no single pathogenetically relevant mechanism has yet been confirmed for MS. In summary we presently may assume only subtle effects of the apoE polymorphism on the course of MS. These effects are probably further modulated by other genes and need further investigation.

Alzheimer Disease↗
PubMed2006

Subcortical vascular cognitive impairment: similarities and differences with multiple sclerosis.

Subcortical vascular cognitive impairment is caused by lacunes and widespread ischemic white matter damage which closely resembles white matter abnormalities seen in multiple sclerosis. Recent evidence suggests that the progression rate of ischemic white matter lesions on MRI is very similar to that observed in multiple sclerosis. Consequently, it has been proposed to use MRI for monitoring disease activity not only in multiple sclerosis but also in vascular dementia trials. There is first evidence from magnetization transfer imaging studies that other than in MS normal appearing white matter is not affected in cerebral small vessel disease. This contrasts the hypothesis that ischemic white matter damage extends far beyond changes visible on conventional MR. The cognitive consequences of both diseases are strikingly similar which is at least partly caused by damage to frontal-subcortical circuits. Involvement of these common functional anatomical structures and their modulatory transmitter systems has now led to common interventional approaches such as the use of cholinesterase inhibitors.

Brain Mapping↗
PubMed2006

Lesion probability maps of white matter hyperintensities in elderly individuals: results of the Austrian stroke prevention study.

OBJECTIVE: White matter hyperintensities (WMH) are common on brain MRI of the elderly. Their size ranges from punctate to early confluent to confluent lesions. While this increase in extension is frequently seen as evidence for a continuum of changes, histological data and clinical follow-up suggest differences in underlying pathology and their progression. METHODS: We tested this hypothesis by exploring the distributions of punctuate and confluent lesions using lesion probability maps (LPM) generated from MRI scans of 189 participants (mean age 60.8+/-6.2 years) in the Austrian Stroke Prevention Study. We dichotomised WMH according to the classification by Fazekas et al. [punctate (n=143) vs. early confluent and confluent (n=33)] to run voxel-based t-tests using permutation-based nonparametric inference. To test alternative hypotheses, we created similar LPM for age and arterial hypertension. RESULTS: We observed significant differences in the spatial distribution of lesions for the two WMH groups (p<0.01). Punctate lesions were more diffusely distributed throughout the cerebral white matter (peak probability approximately 5%) relative to confluent lesions (peak probability 45%). Confluent lesions had greatest likelihood of being found in perfusion "watershed" regions. These differences in distribution could not be explained by differences in age or hypertension only, as both greater age and the diagnosis of hypertension were associated with WMH abutting the occipital horns. CONCLUSIONS: Punctate and early confluent to confluent WMH show distinguishable differences in their spatial distribution within a normal elderly population. The pattern of punctate WMH is probably a consequence of mixed etiologies. Preferential localization of the more confluent WMH with arterial watershed areas implies a stronger ischemic component in their development.

Age Factors↗
PubMed2006

Secondary prevention of stroke in patients with atrial fibrillation: factors influencing the prescription of oral anticoagulation at discharge.

BACKGROUND: Oral anticoagulation (OAC) is the only treatment that has shown a significant benefit to reduce the risk of recurrence in patients with ischemic stroke and nonvalvular atrial fibrillation (NVAF). However, OAC is still underused, even at discharge from neurological centers. The objective of this study was to identify the reasons underlying the prescription of OAC at discharge after an ischemic stroke in patients with NVAF. METHODS: We investigated the reasons why ischemic stroke patients with NVAF were not treated with OAC at discharge from 40 centers located in 5 European countries (Austria, Belgium, France, Italy, and Portugal). RESULTS: Of 320 ischemic stroke survivors at discharge, 186 (58.1%) received OAC, while 260 (81.3%) patients were theoretically eligible according to guidelines and the absence of contraindications. There were significant differences between countries and the logistic regression analysis found being already under OAC before stroke, having no leukoaraiosis, having no potential contraindication, being younger than 75 years, being married and suffering from angina pectoris as independent predictors of being discharged under OAC. CONCLUSION: This study suggests that besides patient-related factors, the prescription of OAC is also significantly influenced by the social environment and national practices.

Administration, Oral↗
PubMed2006

Impact of white matter hyperintensities scoring method on correlations with clinical data: the LADIS study.

BACKGROUND AND PURPOSE: White matter hyperintensities (WMH) are associated with decline in cognition, gait, mood, and urinary continence. Associations may depend on the method used for measuring WMH. We investigated the ability of different WMH scoring methods to detect differences in WMH load between groups with and without symptoms. METHODS: We used data of 618 independently living elderly with WMH collected in the Leukoaraiosis And DISability (LADIS) study. Subjects with and without symptoms of depression, gait disturbances, urinary incontinence, and memory decline were compared with respect to WMH load measured qualitatively using 3 widely used visual rating scales (Fazekas, Scheltens, and Age-Related White Matter Changes scales) and quantitatively with a semiautomated volumetric technique and an automatic lesion count. Statistical significance between groups was assessed with the chi2 and Mann-Whitney tests. In addition, the punctate and confluent lesion type with comparable WMH volume were compared with respect to the clinical data using Student t test and chi2 test. Direct comparison of visual ratings with volumetry was done using curve fitting. RESULTS: Visual and volumetric assessment detected differences in WMH between groups with respect to gait disturbances and age. WMH volume measurement was more sensitive than visual scores with respect to memory symptoms. Number of lesions nor lesion type correlated with any of the clinical data. For all rating scales, a clear but nonlinear relationship was established with WMH volume. CONCLUSIONS: Visual rating scales display ceiling effects and poor discrimination of absolute lesion volumes. Consequently, they may be less sensitive in differentiating clinical groups.

Aged↗
PubMed2006

Cerebral changes on MRI and cognitive function: the CASCADE study.

The aging, non-demented brain undergoes several physiological changes, some of which may affect cognitive function. The goal of the present study was to examine the associations between subcortical and periventricular white matter hyperintensities (WMHs), cortical and subcortical atrophy, and cognitive function (episodic memory, word fluency, attention, and perceptual, cognitive, and motor speed). This was done within a European collaborative study, Cardiovascular Determinants of Dementia (CASCADE), in which magnetic resonance imaging (MRI) was performed on community-dwelling individuals. The study includes 1254 persons from eight European study centers, ranging between 64 and 76 years of age (M 69.4+/-3.3; 55% men). When demographics (age, education, and sex), study center, and concurrent brain changes had been adjusted for, periventricular WMHS predicted lower performance in word fluency and the Stroop test (time), and subcortical atrophy predicted lower performance in motor speed and the Stroop test (errors). The findings are consistent with findings from lesion and functional neuroimaging studies.

Age Distribution↗
PubMed2006

Pulmonary surfactant in patients with Pneumocystis pneumonia and acquired immunodeficiency syndrome.

OBJECTIVE: Pneumocystis pneumonia (PCP) is a severe infection of the immunocompromised host, resulting in diffuse alveolar damage and life-threatening respiratory failure. We analyzed pulmonary surfactant composition and function in bronchoalveolar lavage fluid (BALF) from ventilated and spontaneously breathing HIV-positive patients with PCP. DESIGN: Prospective clinical trial. SETTING: University hospital intensive care unit. PATIENTS: Thirty-four spontaneously breathing (SB-PCP) and 20 ventilated HIV-positive patients with PCP (V-PCP), ten patients with acute respiratory distress syndrome (ARDS), 11 spontaneously breathing patients with bacterial pneumonia (PNEU), and 22 healthy volunteers. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Total phospholipid in BALF did not differ between any category vs. controls, whereas total protein increased approximately 14-fold in V-PCP and five-fold in SB-PCP compared with controls (p < .001). The relative content of large surfactant aggregates (LA) was reduced in SB-PCP and V-PCP compared with controls (p < .05). The phospholipid and fatty acid profiles showed a significant reduction in the relative content of phosphatidylcholine (PC), phosphatidylglycerol, and palmitic acid in PC in all patient categories compared with controls, with more in V-PCP (p < .001) compared with SB-PCP (p < .05). The neutral lipid-to-phospholipid ratio in LA was three-fold elevated in V-PCP (p < .01 compared with control) but not in SB-PCP. Analysis of neutral lipid classes showed a significant increase in the relative content of triglycerides and a reduction in free fatty acids in V-PCP compared with controls. BALF surfactant protein (SP)-A and SP-D significantly increased in V-PCP and SB-PCP, but not in ARDS and PNEU, compared with controls (p < .05). SP-B and SP-C content in LA remained unchanged in PCP compared with controls but decreased significantly in ARDS and PNEU. The minimum surface tension of LA was impaired (p < .001) in V-PCP more than in SB-PCP and was strongly correlated with the reduction in palmitic acid levels in PC LA (r = -.81). Reductions in phosphatidylglycerol strongly correlated with decreased Pao2/Fio2 values (r = .72). CONCLUSIONS: We conclude that severe alterations in surfactant function and composition occur in patients with PCP and are even more pronounced in ventilated patients than in nonventilated patients. Surfactant lipid changes in PCP, but not surfactant protein profiles, closely resemble those found in ARDS.

AIDS-Related Opportunistic Infections↗
PubMed2006

Leukoaraiosis predicts hidden global functioning impairment in nondisabled older people: the LADIS (Leukoaraiosis and Disability in the Elderly) Study.

OBJECTIVES: To determine whether leukoaraiosis severity is independently associated with differences in global functioning in nondisabled elderly patients. DESIGN: Cross-sectional data analysis from an ongoing longitudinal multicenter and multinational study. SETTING: The Leukoaraiosis and Disability Study, a collaboration aimed at assessing leukoaraiosis as an independent predictor of the transition to disability in older people. PARTICIPANTS: Six hundred thirty-nine nondisabled subjects (288 men, 351 women, mean age+/-standard deviation 74.1+/-5.0) with magnetic resonance imaging-detected leukoaraiosis of different severity and presenting with one of the following: mild cognitive or motor disturbances, minor cerebrovascular events, or mood alterations or in whom leukoaraiosis was incidentally identified. MEASUREMENTS: Centralized assessment of leukoaraiosis severity according to the three severity degrees of the Fazekas scale; Disability Assessment for Dementia (DAD) Scale for measurement of global functioning. RESULTS: At baseline, 44% of participants had a mild, 31% a moderate, and 25% a severe degree of leukoaraiosis. A significant trend toward declining performance on the DAD Scale was apparent with increasing leukoaraiosis score severity (total score=98.8, 98.6, 97.5, respectively, in the three leukoaraiosis categories, analysis of variance P=.002). Similar trends were obtained for basic (P=.01) and instrumental (P<.001) function items. The statistical significance of these differences was confirmed in a multiple linear regression analysis correcting for numerous factors known to influence disability in older people. Executive function test performance declined along with increasing leukoaraiosis severity and was significantly related to DAD total score. CONCLUSION: Even in nondisabled elderly patients, levels of functional ability are related to white matter lesion severity. Executive dysfunction may mediate this relationship.

Activities of Daily Living↗
PubMed2005

Sequential analysis of surfactant, lung function and inflammation in cystic fibrosis patients.

BACKGROUND: In a cross-sectional analysis of cystic fibrosis (CF) patients with mild lung disease, reduced surfactant activity was correlated to increased neutrophilic airway inflammation, but not to lung function. So far, longitudinal measurements of surfactant function in CF patients are lacking and it remains unclear how these alterations relate to the progression of airway inflammation as well as decline in pulmonary function over time. METHODS: As part of the BEAT trial, a longitudinal study to assess the course of airway inflammation in CF, we studied lung function, surfactant function and endobronchial inflammation using bronchoalveolar lavage fluid from 20 CF patients with normal pulmonary function (median FEV1 94% of predicted) at three times over a three year period. RESULTS: There was a progressive loss of surfactant function, assessed as minimal surface tension. The decline in surfactant function was negatively correlated to an increase in neutrophilic inflammation and a decrease in lung function, assessed by FEV1, MEF(75/25%VC), and MEF(25%VC). The concentrations of the surfactant specific proteins A, C and D did not change, whereas SP-B increased during this time period. CONCLUSION: Our findings suggest a link between loss of surfactant function driven by progressive airway inflammation and loss of small airway function in CF patients with limited lung disease.

Cross-Sectional Studies↗
PubMed2005

Small vessel disease and general cognitive function in nondisabled elderly: the LADIS study.

BACKGROUND AND PURPOSE: On cerebral magnetic resonance imaging (MRI), white matter hyperintensities (WMH) and lacunes are generally viewed as evidence of small vessel disease. The clinical significance of small vessel disease in terms of global cognitive function has as yet not been completely clarified. We investigated the independent contribution of WMH and lacunes to general cognitive function in a group of independently living elderly with varying degrees of small vessel disease. METHODS: Data were drawn from the multicenter, multinational Leukokraurosis and Disability (LADIS) study. There were 633 independently living participants. General cognitive function was assessed using the Mini Mental State Examination (MMSE) and the modified Alzheimer Disease Assessment Scale (ADAS). On MRI, WMH was rated as mild, moderate, or severe. Lacunes were rated as none, few (1 to 3), or many (4 or more). RESULTS: In the basic analysis, increasing severity of both WMH and lacunes was related to deteriorating score on the MMSE and ADAS. When WMH and lacunes were entered simultaneously, both MRI measures remained significantly associated with MMSE score. Increasing severity of WMH remained associated with ADAS score, whereas the association with lacunes became less prominent. These associations were independent of other risk factors for dementia, like education, depression, vascular risk factors, or stroke. CONCLUSIONS: We found WMH and lacunes to be independently associated with general cognitive function in a sample of independently living elderly. These results highlight the fact that WMH and lacunes should both be evaluated when assessing small vessel disease in relation to cognitive function.

Aged↗
PubMed2005

MTI of white matter hyperintensities.

The severity of tissue changes associated with incidental white matter hyperintensities (WMH) in the elderly cannot be sufficiently determined by conventional MRI. We, therefore, performed a regional analysis of the magnetization transfer ratio (MTR) maps obtained on a 1.5 T scanner from 198 neurologically asymptomatic participants of the Austrian Stroke Prevention Study (mean age 70, age range 52-87 years) in regard to WMH and predefined areas of normal appearing brain tissue. Fluid attenuated inversion recovery MRI was used to grade lesion severity and for lesion volume measurements. The MTR of WMH was always significantly lower than that of normal appearing white matter (NAWM) with an overall relative reduction of approximately 10% and decreased significantly with increasing scores of WMH severity (P = 0.02) and WMH volume (r = -0.24, P = 0.0016). NAWM MTR was not different between subjects with very few and extensive WMH and the WMH volume was associated with NAWM MTR of the frontal lobes only. Concerning a possible impact on cerebral functioning the MTR of the frontal NAWM was significantly associated with fine motor dexterity (P = 0.04) but not with cognitive performance. A significant decline of the MTR with aging was seen in both NAWM and cortex but not in WMH. We conclude that MTR measurements can serve to quantify WMH associated tissue damage. It is predominantly focal, relatively mild, increases with lesion size and may have remote effects on the frontal white matter.

Aged↗
PubMed2005

Markers of endothelial and hemostatic activation and progression of cerebral white matter hyperintensities: longitudinal results of the Austrian Stroke Prevention Study.

BACKGROUND AND PURPOSE: The pathogenesis of cerebral small vessel disease (SVD) is poorly understood, but endothelial activation and dysfunction may play a causal role. Cross-sectional studies have found increased circulating markers of endothelial activation, but this study design cannot exclude causality from secondary elevations. Confluent white matter hyperintensities (WMHs) on magnetic resonance imaging (MRI) appear to represent asymptomatic cerebral SVD. In a prospective study, we determined whether circulating markers of endothelial activation predicted progression of WMH. METHODS: In the community-based Austrian Stroke Prevention Study, MRI was performed at baseline in 296 subjects and repeated at 3 and 6 years. The following were measured on baseline plasma samples: intercellular adhesion molecule (ICAM), thrombomodulin, tissue factor plasma inhibitor, prothrombin fragments 1 and 2, and D-dimers. RESULTS: ICAM was associated with age- and gender-adjusted WMH lesion progression at both 3 and 6 years, respectively; (odds ratio [OR], 1.007; 95% confidence interval [CI], 1.002 to 1.012; P=0.004; and OR, 1.004; 95% CI, 1.000 to 1.009 per ng/mL; P=0.057). After multivariate analysis controlling for other cardiovascular risk factors and C-reactive protein, 3-year OR was 1.010 (95% CI, 1.004 to 1.017; P=0.001) and 6-year OR was 1.008 (1.002 to 1.014 per ng/mL; P=0.006). Baseline log lesion volume was a strong independent predictor of progression but associations remained after controlling for this (3-year OR, 1.011; 95% CI, 1.002 to 1.020; P=0.013; and 6-year OR, 1.009; 95% CI, 1.000 to 1.017; P=0.039 per ng/mL). There was no association between WMH progression and other markers. CONCLUSIONS: ICAM levels are related to progression of WMH on MRI. The prospective study design increases the likelihood that this association is causal and supports a role of endothelial cell activation in disease pathogenesis. In contrast, we found no evidence for coagulation activation being important.

Aged↗
PubMed2005

Secondary prevention after cryptogenic cerebrovascular events in patients with patent foramen ovale.

BACKGROUND: Patients with patent foramen ovale and cryptogenic stroke are at risk of recurrence, but there are few data on strategies to prevent this. METHODS: We studied 280 consecutive patients with cryptogenic cerebrovascular events and a patent foramen ovale examined by multiplane transesophageal echocardiography. Patients received platelet inhibitors (n = 66) or anticoagulation (n = 47) or underwent device closure (n = 167). During the mean follow-up of 2.6 years, we compared the frequency of recurrent events, death and severe treatment complications. RESULTS: A total of 33 (12%) patients had a recurrent cerebrovascular event. The annual recurrence rates were 13% in patients treated with platelet inhibitors, 5.6% in those on oral anticoagulation, and 0.6% in those after device closure. Independent predictors of recurrent cerebrovascular events were a patent foramen ovale larger than 4 mm (hazard ratio 3.8, 95% CI 1.2-11.2; p = 0.017) or previous strokes (hazard ratio 4.3, 95% CI 2.0-9.2; p < 0.001). Interventional closure of the patent foramen ovale decreased the risk of a recurrent event compared with oral anticoagulation (hazard ratio 0.06, 95% CI 0.12-0.29; p < 0.001), whereas antiplatelet therapy showed a trend to an increased risk (hazard ratio 2.3; 95% CI 0.9-5.5; p = 0.055). Major side effects occurred in 7 anticoagulated patients and in 13 patients after device closure. There were two non-vascular deaths and one fatal hemorrhagic stroke. CONCLUSIONS: Patients with a large patent foramen ovale and a cryptogenic cerebrovascular event had a substantial risk of recurrence even with medical treatment. Risk of recurrence was lower after device closure of the patent foramen ovale.

Adult↗
PubMed2005

White matter lesion progression, brain atrophy, and cognitive decline: the Austrian stroke prevention study.

White matter lesions progress over time, but the clinical consequences are widely unknown. Three-hundred twenty-nine elderly community-dwelling volunteers underwent serial magnetic resonance imaging scanning and cognitive testing at baseline and at 3- and 6-year follow-up. We measured the changes in white matter lesion and brain parenchymal volumes. After 6 years, the median increase in white matter lesion load was 0.2 cm3 (interquartile range [IQR], 0.0-0.80 cm3) with a maximum of 31.4 cm3. The median loss of brain volume was 2.3% (IQR, 1.13-3.58%). Increasing white matter lesion volume was correlated with loss of brain volume (p < 0.0001) and performance decline in tests of memory (p = 0.022), conceptualization (p = 0.046), and visuopractical skills (p = 0.005). Associations between changes in white matter lesion load and cognitive functioning were no longer significant when adding change in brain volume to the models, suggesting that cognitive decline related directly to loss of brain substance with progression of lesion burden.

Aged↗