Anita Lechner

MRI evidence of past cerebral microbleeds in a healthy elderly population

Background: Incidental foci of signal loss suggestive of past microbleeds are a frequent finding on gradient-echo T2*-weighted MRI of patients with nontraumatic intracerebral hemorrhage and have been associated with bleeding-prone microangiopathy. If and to what extent such lesions may also occur in the normal population is unclear. Objective: To determine focal hypointensities in asymptomatic elderly individuals and their relation to other clinical and morphologic variables. Methods: T2*-weighted MRI of the brain was performed in a consecutive series of 280 participants (mean age 60 years, range 44 to 79) of the Austrian Stroke Prevention Study. This cohort consisted of randomly selected individuals without history or signs of neuropsychiatric disorder. Results: Past microbleeds ranging from one to five foci of signal loss were seen in 18 (6.4%) individuals. They were strongly associated with higher age, hypertension, and lacunes (p < 0.001), and extensive white matter damage was more frequently noted (p = 0.02). Hypertension was present in all individuals with focal hypointensities in the basal ganglia and infratentorially but in only 5 of 10 volunteers with microbleeds limited to cortico-subcortical sites (p = 0.04). Conclusions: MRI evidence of past microbleeds may be found even in neurologically normal elderly individuals and is related, but not restricted, to other indicators of small vessel disease. The predictive potential of this finding regarding the risk of intracerebral bleeding requires further investigation.

Frequency and Location of Microbleeds in Patients With Primary Intracerebral Hemorrhage

Background and Purpose MRI is known to detect clinically silent microbleeds (MBs) in patients with primary intracerebral hemorrhage (pICH), but the frequency and diagnostic and clinical significance of this finding are still debated. Therefore, we investigated a consecutive series of pICH patients and analyzed the patterns of MB distribution in the context of clinical variables and location of the symptomatic hematoma. Methods The study population consisted of 109 patients with pICH. There were 59 women and 50 men aged 22 to 91 years (mean 64.6 years). MRI was obtained on a 1.5-T system with use of a gradient-echo T2*-weighted sequence. A cohort of 280 community-dwelling asymptomatic elderly individuals who underwent the same imaging protocol served for comparison. Results MBs were seen in 59 (54%) patients and ranged in number from 1 to 90 lesions (mean 14, median 6). In the majority of patients, MBs were located simultaneously in various parts of the brain, with a preference for cortical-subcortical regions (39%) and the basal ganglia/thalami (38%). There was some tendency toward a regional association between MB location and the site of the symptomatic hematoma, but we could not discern specific patterns of MB distribution. Logistic regression analysis identified MBs, periventricular hyperintensity grades, and lacunes but not risk factors as independent variables contributing to a correct classification of pICH and control individuals. Conclusions MBs can be detected in more than half of the patients with pICH and appear to be quite general markers of various types of bleeding-prone microangiopathy.

Angiotensinogen Polymorphism M235T, Carotid Atherosclerosis, and Small-Vessel Disease-Related Cerebral Abnormalities

The angiotensinogen M235T polymorphism has been linked to hypertension and cardiovascular disease. We studied the role of this polymorphism as a risk factor for carotid atherosclerosis and small-vessel disease-related brain abnormalities. A total of 431 randomly selected community-dwelling subjects without clinical evidence for strokes underwent angiotensinogen genotyping and carotid Duplex scanning; 1.5-T brain magnetic resonance imaging (MRI) was done in 396 individuals. At 3-year follow-up, we reexamined 343 and 267 study participants by ultrasound and brain MRI, respectively. Carotid atherosclerosis was graded on a 5-point scale. Small-vessel disease-related brain abnormalities were deep or subcortical white matter lesions or lacunes. Progression of carotid atherosclerosis and MRI findings was rated by direct imaging comparison by 3 independent raters. The M/M, M/T, and T/T genotypes were seen in 20.9%, 52.9%, and 18.1% of subjects, respectively. The M235T polymorphism was neither associated with baseline carotid findings nor with progression of carotid atherosclerosis. There was a trend toward more frequent small-vessel disease-related MRI abnormalities in the T/T than in the other genotypes at the baseline examination. Progression of brain lesions occurred significantly more commonly in T/T than in M/M and M/T carriers (P <0.001). Logistic regression analysis identified the T/T genotype (odds ratio, 3.19;P =0.002) and arterial hypertension (odds ratio, 3.06;P =0.03) as significant independent predictors of lesion progression. These data suggest that the angiotensinogen T/T genotype at position 235 is a genetic marker for brain lesions from and progression of small vessel disease but not for extracranial carotid atherosclerosis.

MRI Cerebral White Matter Lesions and Paraoxonase PON1 Polymorphisms Three-Year Follow-Up of the Austrian Stroke Prevention Study

White matter lesions (WMLs) on magnetic resonance imaging (MRI) scans of older persons are thought to be caused by cerebral small-vessel disease. As they progress, these brain abnormalities frequently result in cognitive decline and gait disturbances, and their predictors are incompletely understood. Genetic risk factors have been implicated but remain undetermined so far. We examined whether 2 common polymorphisms of the paraoxonase (PON1) gene leading to a methionine (M allele)-leucine (L allele) interchange at position 54 and an arginine (B allele)-glutamine (A allele) interchange at position 191 are associated with the presence and progression of WMLs. We studied 264 community-dwelling subjects without neuropsychiatric disease (ages 44 to 75 years). All underwent vascular risk factor assessment, brain MRI, and PON1 genotyping. MRI scanning was repeated after 3 years. The extent and number of WMLs were recorded by 3 independent readers. Progression of WMLs was assessed by direct scan comparison. The final rating relied on the majority judgment of the 3 readers. The LL, LM, and MM genotypes were noted in 111 (42.0%), 118 (44.7%), and 35 (13.3%) subjects, respectively; the AA, AB, and BB genotypes occurred in 146 (55.3%), 98 (37.1%), and 20 (7.8%) individuals, respectively. Carriers of the LL genotype showed a nonsignificant trend toward more extensive WMLs and more frequently demonstrated lesion progression over the 3-year observation period (P=0.03). The polymorphism at position 191 had no effect. Logistic regression analysis yielded age (odds ratio, 1.08/y), diastolic blood pressure (odds ratio, 1.05/mm Hg), and LL paraoxonase genotype (odds ratio, 2. 65) to be significant predictors of WML progression. These data suggest that the LL PON1 genotype at position 54 influences the extent and progression of WMLs in elderly subjects.

Driving cessation and dementia: results of the prospective registry on dementia in Austria (PRODEM).

Objective To assess the influence of cognitive, functional and behavioral factors, co-morbidities as well as caregiver characteristics on driving cessation in dementia patients. Methods The study cohort consists of those 240 dementia cases of the ongoing prospective registry on dementia in Austria (PRODEM) who were former or current car-drivers (mean age 74.2 (±8.8) years, 39.6% females, 80.8% Alzheimer’s disease). Reasons for driving cessation were assessed with the patients’ caregivers. Standardized questionnaires were used to evaluate patient- and caregiver characteristics. Cognitive functioning was determined by Mini-Mental State Examination (MMSE), the CERAD neuropsychological test battery and Clinical Dementia Rating (CDR), activities of daily living (ADL) by the Disability Assessment for Dementia, behavior by the Neuropsychiatric Inventory (NPI) and caregiver burden by the Zarit burden scale. Results Among subjects who had ceased driving, 136 (93.8%) did so because of “Unacceptable risk” according to caregiver’s judgment. Car accidents and revocation of the driving license were responsible in 8 (5.5%) and 1(0.7%) participant, respectively. Female gender (OR 5.057; 95%CI 1.803–14.180; p = 0.002), constructional abilities (OR 0.611; 95%CI 0.445–0.839; p = 0.002) and impairment in Activities of Daily Living (OR 0.941; 95%CI 0.911–0.973; p<0.001) were the only significant and independent associates of driving cessation. In multivariate analysis none of the currently proposed screening tools for assessment of fitness to drive in elderly subjects including the MMSE and CDR were significantly associated with driving cessation. Conclusion The risk-estimate of caregivers, but not car accidents or revocation of the driving license determines if dementia patients cease driving. Female gender and increasing impairment in constructional abilities and ADL raise the probability for driving cessation. If any of these factors also relates to undesired traffic situations needs to be determined before recommendations for their inclusion into practice parameters for the assessment of driving abilities in the elderly can be derived from our data.

Evolution of White Matter Lesions

A 3-year follow-up of 273 participants (mean age 60 years) of the Austrian Stroke Prevention Study provides first information on the rate, clinical predictors and cognitive consequences of MRI white matter lesions (WML) in elderly individuals without neuropsychiatric disease. Lesion progression was found in 17.9% of individuals over a time period of 3 years. Diastolic blood pressure and early confluent or confluent white matter hyperintensities at baseline were the only significant predictors of white matter hyperintensity progression. Genetic association studies in the setting of the Austrian Stroke Prevention Study provide first evidence for genetic susceptibility factors for progression of WML. We observed associations with the paraoxonase Leu→Met 54 polymorphism and with the M235T polymorphism of the angiotensinogen gene. Lesion progression had no influence on the course of neuropsychologic test performance over the observational period, but the statistical power of this analysis was low.

Lipid profile in normal weight migraineurs – evidence for cardiovascular risk

Background:  Recent studies suggest that migraine is associated with metabolic disorders. In particular, migraine may be associated with cardiovascular risk; however, an association of migraine with cardiovascular risk factors like hypercholesterolemia has been proposed, but previous studies have yielded in part conflicting results. The aim of the present study is to evaluate the lipid profile in normal weight migraine patients.

Oxidative stress is associated with migraine and migraine-related metabolic risk in females.

Background and purpose:  Oxidative stress is discussed to be implicated in the pathophysiology of migraine. However, data are in part controversial and the possible underlying mechanisms remain elusive to date. The aim of this study was to investigate the oxidative stress status of female patients with migraine and its implications on migraine‐related metabolic alterations.

Increased nitric oxide stress is associated with migraine

Nitric oxide (NO) has been implicated in migraine attacks, but the role of NO in migraine remains unclear. We here hypothesize that increased NO in the headache-free period is associated with migraine. One hundred and thirty probands participated in this study. Various parameters of the NO pathway, such as nitrate, nitrite, arginine, citrulline, nitrosylated proteins, asymmetric dimethylarginine, symmetrical dimethylarginine, expression of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase and two polymorphisms of eNOS were investigated. We found significant increased nitrate and decreased nitrite levels in migraineurs in the headache-free period. Nitrate and nitrite levels showed a significant inverse correlation. Logistic regression revealed an odds ratio of 3.6 for migraine. Other parameters of the NO pathway were neither altered in migraineurs nor correlated with nitrate. We show here that migraine patients suffer under sustained increased nitrosative stress in the headache-free period, which is associated with a 3.6-fold higher risk for migraine.

Combining anatomical, diffusion, and resting state functional magnetic resonance imaging for individual classification of mild and moderate Alzheimer's disease

Magnetic resonance imaging (MRI) is sensitive to structural and functional changes in the brain caused by Alzheimers disease (AD), and can therefore be used to help in diagnosing the disease. Improving classification of AD patients based on MRI scans might help to identify AD earlier in the diseases progress, which may be key in developing treatments for AD. In this study we used an elastic net classifier based on several measures derived from the MRI scans of mild to moderate AD patients (N = 77) from the prospective registry on dementia study and controls (N = 173) from the Austrian Stroke Prevention Family Study. We based our classification on measures from anatomical MRI, diffusion weighted MRI and resting state functional MRI. Our unimodal classification performance ranged from an area under the curve (AUC) of 0.760 (full correlations between functional networks) to 0.909 (grey matter density). When combining measures from multiple modalities in a stepwise manner, the classification performance improved to an AUC of 0.952. This optimal combination consisted of grey matter density, white matter density, fractional anisotropy, mean diffusivity, and sparse partial correlations between functional networks. Classification performance for mild AD as well as moderate AD also improved when using this multimodal combination. We conclude that different MRI modalities provide complementary information for classifying AD. Moreover, combining multiple modalities can substantially improve classification performance over unimodal classification.