Cognitive trajectory in the first year after first-ever ischaemic stroke in young adults: the ODYSSEY study.

BACKGROUND: Limited data exists on cognitive recovery in young stroke patients. We aimed to investigate the longitudinal course of cognitive performance during the first year after stroke at young age and identify predictors for cognitive recovery. METHODS: We conducted a multicentre prospective cohort study between 2013 and 2021, enrolling patients aged 18-49 years with first-ever ischaemic stroke. Cognitive assessments were performed within 6 months and after 1 year following the index event, covering seven cognitive domains. Composite Z-scores using normative data determined cognitive impairment (Z-score<-1.5). A Reliable Change Index (RCI) assessed cognitive recovery (RCI>1.96) or decline (RCI<-1.96). RESULTS: 393 patients (median age 44.3 years, IQR 38.4-47.2) completed cognitive assessments with a median time interval of 403 days (IQR 364-474) between assessments. Based on RCI, a similar proportion of patients showed improvement and decline in each cognitive domain, while the majority exhibited no cognitive change. Among cognitively impaired patients at baseline, improvements were observed in processing speed (23.1%), visuoconstruction (40.1%) and executive functioning (20.0%). Younger age was associated with better cognitive recovery in visuoconstruction, and larger lesion volume was related to cognitive recovery in processing speed. No other predictors for cognitive recovery were identified. CONCLUSIONS: Cognitive impairment remains prevalent in young stroke even 1 year after the event. Most patients showed no cognitive change, however, recovery may have occurred in the early weeks after stroke, which was not assessed in our study. Among initially cognitively impaired patients, cognitive recovery is observed in processing speed, visuoconstruction and executive functioning. It is still not possible to predict cognitive recovery in individual patients.

Risk Factors and Causes of Ischemic Stroke in 1322 Young Adults.

BACKGROUND: Identification of risk factors and causes of stroke is key to optimize treatment and prevent recurrence. Up to one-third of young patients with stroke have a cryptogenic stroke according to current classification systems (Trial of ORG 10172 in Acute Stroke Treatment [TOAST] and atherosclerosis, small vessel disease, cardiac pathology, other causes, dissection [ASCOD]). The aim was to identify risk factors and leads for (new) causes of cryptogenic ischemic stroke in young adults, using the pediatric classification system from the IPSS study (International Pediatric Stroke Study). METHODS: This is a multicenter prospective cohort study conducted in 17 hospitals in the Netherlands, consisting of 1322 patients aged 18 to 49 years with first-ever, imaging confirmed, ischemic stroke between 2013 and 2021. The main outcome was distribution of risk factors according to IPSS classification in patients with cryptogenic and noncryptogenic stroke according to the TOAST and ASCOD classification. RESULTS: The median age was 44.2 years, and 697 (52.7%) were men. Of these 1322 patients, 333 (25.2%) had a cryptogenic stroke according to the TOAST classification. Additional classification using the ASCOD criteria reduced the number patients with cryptogenic stroke from 333 to 260 (19.7%). When risk factors according to the IPSS were taken into account, the number of patients with no potential cause or risk factor for stroke reduced to 10 (0.8%). CONCLUSIONS: Among young adults aged 18 to 49 years with a cryptogenic ischemic stroke according to the TOAST classification, risk factors for stroke are highly prevalent. Using a pediatric classification system provides new leads for the possible causes in cryptogenic stroke, and could potentially lead to more tailored treatment for young individuals with stroke.

Ipsilateral hippocampal atrophy is associated with long-term memory dysfunction after ischemic stroke in young adults.

Memory impairment after stroke in young adults is poorly understood. In elderly stroke survivors memory impairments and the concomitant loss of hippocampal volume are usually explained by coexisting neurodegenerative disease (e.g., amyloid pathology) in interaction with stroke. However, neurodegenerative disease, such as amyloid pathology, is generally absent at young age. Accumulating evidence suggests that infarction itself may cause secondary neurodegeneration in remote areas. Therefore, we investigated the relation between long-term memory performance and hippocampal volume in young patients with first-ever ischemic stroke. We studied all consecutive first-ever ischemic stroke patients, aged 18-50 years, admitted to our academic hospital center between 1980 and 2010. Episodic memory of 173 patients was assessed using the Rey Auditory Verbal Learning Test and the Rey Complex Figure and compared with 87 stroke-free controls. Hippocampal volume was determined using FSL-FIRST, with manual correction. On average 10 years after stroke, patients had smaller ipsilateral hippocampal volumes compared with controls after left-hemispheric stroke (5.4%) and right-hemispheric stroke (7.7%), with most apparent memory dysfunctioning after left-hemispheric stroke. A larger hemispheric stroke was associated with a smaller ipsilateral hippocampal volume (b=-0.003, P<0.0001). Longer follow-up duration was associated with smaller ipsilateral hippocampal volume after left-hemispheric stroke (b=-0.028 ml, P=0.002) and right-hemispheric stroke (b=-0.015 ml, P=0.03). Our results suggest that infarction is associated with remote injury to the hippocampus, which may lower or expedite the threshold for cognitive impairment or even dementia later in life.

Short-Term and Long-Term Risk of Recurrent Vascular Event by Cause After Ischemic Stroke in Young Adults.

Importance: Cause of ischemic stroke in young people is highly variable; however, the risk of recurrence is often presented with all subtypes of stroke grouped together in classification systems such as the Trial of ORG (danaparoid sodium [Orgaran]) 10172 in Acute Stroke Treatment (TOAST) criteria, which limits the ability to individually inform young patients with stroke about their risk of recurrence. Objective: To determine the short-term and long-term risk of recurrent vascular events after ischemic stroke at a young age by stroke cause and to identify factors associated with recurrence. Design, Setting, and Participants: This cohort study used data from the Observational Dutch Young Symptomatic Stroke Study, a prospective, multicenter, hospital-based cohort study, conducted at 17 hospitals in the Netherlands between 2013 and 2021. Eligible participants included 30-day survivors of an initial, neuroimaging-proven ischemic stroke (aged 18-49 years). Data analysis was conducted from June to July 2023. Exposure: Diagnosis of a first-ever, ischemic stroke via neuroimaging. Main Outcome and Measures: The primary outcome was short-term (within 6 months) and long-term (within 5 years) recurrence risk of any vascular event, defined as fatal or nonfatal recurrent ischemic stroke, transient ischemic attack, myocardial infarction, and revascularization procedure. Predefined characteristics were chosen to identify factors associated with risk of recurrence (cause of stroke, age, sex, stroke severity, and cardiovascular health factors). Results: A total of 1216 patients (median [IQR] age, 44.2 [38.4-47.7] years; 632 male [52.0%]; 584 female [48.0%]) were included, with a median (IQR) follow-up of 4.3 (2.6-6.0) years. The 6-month risk of any recurrent ischemic event was 6.7% (95% CI, 5.3%-8.1%), and the 5-year risk was 12.2% (95% CI, 10.2%-14.2%)The short-term risk was highest for patients with cervical artery dissections (13.2%; 95% CI, 7.6%-18.7%). Other factors associated with a recurrent short-term event were atherothrombotic stroke, rare causes of stroke, and hypertension. The long-term cumulative risk was highest for patients with atherothrombotic stroke (22.7%; 95% CI, 10.6%-34.7%) and lowest for patients with cryptogenic stroke (5.8%; 95% CI, 3.0%-8.5%). Cardioembolic stroke was associated with a recurrent long-term event, as were diabetes and alcohol abuse. Conclusions and Relevance: The findings of this cohort study of 1216 patients with an ischemic stroke at a young age suggest that the risk of recurrent vascular events was high and varied by cause of stroke both for short-term and long-term follow-up, including causes that remained concealed when combined into 1 category in the routinely used TOAST criteria. This knowledge will allow for more personalized counseling of young patients with stroke.

Diffusion tensor imaging and cognition in cerebral small vessel disease: the RUN DMC study.

BACKGROUND: Cerebral small vessel disease (SVD) is very common in elderly and related to cognition, although this relation is weak. This might be because the underlying pathology of white matter lesions (WML) is diverse and cannot be properly appreciated with conventional FLAIR MRI. In addition, conventional MRI is not sensitive to early loss of microstructural integrity of the normal appearing white matter (NAWM), which might be an important factor. Diffusion tensor imaging (DTI) provides alternative information on microstructural white matter integrity and we have used this to investigate the relation between white matter integrity, in both WML and NAWM, and cognition among elderly with cerebral SVD. METHODS: The RUN DMC study is a prospective cohort study among 503 independently living, non-demented elderly with cerebral SVD aged between 50 and 85 years. All subjects underwent MRI and DTI scanning. WML were segmented manually. We measured mean diffusivity (MD) and fractional anisotropy (FA), as assessed by DTI in both WML and NAWM. RESULTS: Inverse relations were found between MD in the WML and NAWM and global cognitive function (ß=-.11, p<0.05; ß=-.18, p<0.001), psychomotor speed (ß=-.15, p<0.01; ß=-.18, p<0.001), concept shifting (ß=-.11, p<0.05; ß=-.10, p<0.05) and attention (ß=-.12, p<0.05; ß=-.15, p<0.001). The relation between DTI parameters in both WML and NAWM and cognitive performance was most pronounced in subjects with severe WML. CONCLUSION: DTI parameters in both WML and NAWM correlate with cognitive performance, independent of SVD. DTI may be a promising tool in exploring the mechanisms of cognitive decline and could function as a surrogate marker for disease progression in therapeutic trials. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.

Trigger Factors for Stroke in Young Adults: A Case-Crossover Study.

BACKGROUND AND OBJECTIVES: Causes of stroke in young adults differ from those in the elderly individuals, and in a larger percentage, no cause can be determined. To gain more insight into the etiology of (cryptogenic) stroke in the young population, we investigated whether trigger factors, such as short-lasting exposure to toxins or infection, may play a role. METHODS: Patients aged 18-49 years with a first-ever ischemic stroke or intracerebral hemorrhage (ICH) in 17 participating centers in the Netherlands completed a questionnaire about exposure to 9 potential trigger factors in hazard periods and on a regular yearly basis. A case-crossover design was used to assess relative risks (RRs) with 95% confidence intervals (95% CIs) by the Mantel-Haenszel case-crossover method, for any stroke (ischemic stroke and ICH combined) and for different etiologic subgroups of ischemic stroke. RESULTS: One thousand one hundred forty-six patients completed the questionnaire (1,043 patients with an ischemic stroke and 103 with an ICH, median age 44.0 years, 52.6% men). For any stroke, an increased risk emerged within 1 hour of cola consumption (RR 2.0, 95% CI 1.5-2.8) and vigorous physical exercise (RR 2.6, 95% CI 2.2-3.0), within 2 hours after sexual activity (RR 2.4, 95% CI 1.6-3.5), within 4 hours after illicit drug use (RR 2.8, 95% CI 1.7-4.9), and within 24 hours after fever or flu-like disease (RR 14.1, 95% CI 10.5-31.2; RR 13.9, 95% CI 8.9-21.9). Four trigger factors increased the risk of other determined and cryptogenic ischemic stroke, 3 that of cardioembolic stroke, 2 that of large vessel atherosclerosis and likely atherothrombotic stroke combined and stroke with multiple causes, and none that of stroke due to small vessel disease. DISCUSSION: We identified cola consumption, vigorous physical exercise, sexual activity, illicit drug use, fever, and flu-like disease as potential trigger factors for stroke in the young population and found differences in the type and number of trigger factors associated with different etiologic subgroups of ischemic stroke. These findings might help in better understanding the pathophysiologic mechanisms of (cryptogenic) stroke in the young population.

Cerebral white matter lesions and lacunar infarcts contribute to the presence of mild parkinsonian signs.

BACKGROUND AND PURPOSE: Mild parkinsonian signs (MPS) are common in elderly people and may be an early stage of parkinson(ism). They might be related to cerebral small-vessel disease, although this association remains incompletely understood. To identify subjects at early stages of the disease, we investigated whether the presence of MPS was dependent on the severity and location of small-vessel disease, including white matter lesions and lacunar infarcts. METHODS: Four hundred thirty individuals, with small-vessel disease, aged between 50 and 85 years, without dementia or parkinsonism, were included in this analysis and underwent MRI scanning. The number and location of lacunar infarcts were rated. White matter lesion volume was assessed by manual segmentation with automated delineating of different regions. Presence of MPS was based on the motor section of the Unified Parkinson's Disease Rating Scale. Associations were determined using logistic regression analysis adjusted for age, sex, and total brain volume. RESULTS: Severe white matter lesions and the presence of lacunar infarcts were independently associated with the presence of MPS (OR, 2.6; 95% CI, 1.3-4.9 and OR, 1.8; 95% CI, 1.0-3.0). Frontal and parietal white matter lesions and, to a lesser extent, lacunar infarcts in the thalamus were associated with a higher risk of MPS. The presence of lacunar infarcts was independently related to the bradykinesia category of parkinsonian signs. CONCLUSIONS: This study shows that severe small-vessel disease, especially at certain locations, is associated with MPS signs in older adults. Our findings suggest that small-vessel disease interrupts basal ganglia-thalamocortical circuits involving both the frontal and parietal lobes and hence may result in MPS.

Diffusion tensor imaging of the hippocampus and verbal memory performance: the RUN DMC study.

BACKGROUND: Cerebral small vessel disease (SVD) and hippocampal atrophy are related to verbal memory failures and may ultimately result in Alzheimer's disease. However, verbal memory failures are often present before structural changes on conventional MRI appear. Changes in microstructural integrity of the hippocampus, which cannot be detected with conventional MRI, may be the underlying pathological substrate. With diffusion tensor imaging (DTI), we investigated the relation between the microstructural integrity of the hippocampus and verbal memory performance in 503 nondemented elderly with SVD. METHODS: The Radboud University Nijmegen Diffusion tensor and Magnetic resonance imaging Cohort study is a prospective cohort study among 503 nondemented elderly with cerebral SVD aged between 50 and 85 years. All participants underwent T1 MPRAGE, fluid-attenuated inversion recovery, DTI scanning and the Rey Auditory Verbal Learning Test. After manual segmentation of the hippocampi, we calculated the mean diffusivity (MD) and fractional anisotropy in both hippocampi. The relation between memory performance and hippocampal DTI parameters was adjusted for age, sex, education, depressive symptoms, hippocampal, and white-matter lesions volume and lacunar infarcts. RESULTS: We found inverse relations between hippocampal MD and verbal memory performance (ß = -0.22; P < 0.001), immediate recall (ß = -0.22; P < 0.001), delayed recall (ß = -0.20; P < 0.001), and forgetting rate (ß = -0.13; P = 0.025), most pronounced in participants with a normal hippocampal volume. CONCLUSION: Microstructural integrity of the hippocampus assessed by DTI is related to verbal memory performance in elderly with SVD, also in participants with an intact appearing hippocampus. Changes in hippocampal microstructure may be an early marker of underlying neurodegenerative disease, before macrostructural (i.e., volumetric) changes occur.

Cigarette smoking is associated with reduced microstructural integrity of cerebral white matter.

Cigarette smoking doubles the risk of dementia and Alzheimer's disease. Various pathophysiological pathways have been proposed to cause such a cognitive decline, but the exact mechanisms remain unclear. Smoking may affect the microstructural integrity of cerebral white matter. Diffusion tensor imaging is known to be sensitive for microstructural changes in cerebral white matter. We therefore cross-sectionally studied the relation between smoking behaviour (never, former, current) and diffusion tensor imaging parameters in both normal-appearing white matter and white matter lesions as well as the relation between smoking behaviour and cognitive performance. A structured questionnaire was used to ascertain the amount and duration of smoking in 503 subjects with small-vessel disease, aged between 50 and 85 years. Cognitive function was assessed with a neuropsychological test battery. All subjects underwent 1.5 Tesla magnetic resonance imaging. Using diffusion tensor imaging, fractional anisotropy and mean diffusivity were calculated in both normal-appearing white matter and white matter lesions. A history of smoking was associated with significant higher values of mean diffusivity in normal-appearing white matter and white matter lesions (P-trend for smoking status = 0.02) and with poorer cognitive functioning compared with those who never smoked. Associations with smoking and loss of structural integrity appeared to be strongest in normal-appearing white matter. Furthermore, the duration of smoking cessation was positively related to lower values of mean diffusivity and higher values of fractional anisotropy in normal-appearing white matter [ß = -0.004 (95% confidence interval -0.007 to 0.000; P = 0.03) and ß = 0.019 (95% confidence interval 0.001-0.038; P = 0.04)]. Fractional anisotropy and mean diffusivity values in normal-appearing white matter of subjects who had quit smoking for >20 years were comparable with subjects who had never smoked. These data suggest that smoking affects the microstructural integrity of cerebral white matter and support previous data that smoking is associated with impaired cognition. Importantly, they suggest that quitting smoking may reverse the impaired structural integrity.

Diffusion tensor imaging and gait in elderly persons with cerebral small vessel disease.

BACKGROUND AND PURPOSE: Although cerebral small vessel disease, including white matter lesions (WML) and lacunar infarcts, is associated with gait disturbances, not all individuals with small vessel disease have these disturbances. Identical-appearing WML on MRI could reflect different degrees of microstructural integrity. Moreover, conventional MRI does not assess the integrity of normal-appearing white matter (NAWM). We therefore investigated the relation between white matter integrity assessed by diffusion tensor imaging in WML, NAWM, several regions of interest, and gait. METHODS: A total of 484 nondemented elderly persons between 50 and 85 years old with cerebral small vessel disease were included in this analysis and underwent MRI and diffusion tensor imaging scanning. Mean diffusivity and fractional anisotropy within WML, NAWM, and regions of interest were related to quantitative and semiquantitative gait parameters. RESULTS: Mean diffusivity in the WML was inversely related with gait (velocity ß=-0.15; P=0.002). For the fractional anisotropy, this relation was less evident. The same was found in the NAWM (velocity ß=-0.21; P<0.001) and for some parameters also after additional adjustment for WML and lacunar infarcts. CONCLUSIONS: This study indicates that integrity of both WML and NAWM, beyond the detection limit of conventional MRI, is associated with gait disturbances.

Gait in elderly with cerebral small vessel disease.

BACKGROUND AND PURPOSE: Gait disorders are common in the elderly and are related to loss of functional independence and death. White matter lesions (WMLs) may be related, but only a minority of individuals with WMLs has gait disorders. Probably other factors are involved, including location and the independent effect of frequently coinciding lacunar infarcts, the other aspect of cerebral small vessel disease. The aim of our study was to investigate the effect of both the severity and location of both WMLs and lacunar infarcts on gait. METHODS: Four hundred thirty-one independently living, nondemented elderly aged between 50 and 85 years with cerebral small vessel disease were included in this analysis and underwent MRI scanning. The number and location of lacunar infarcts were rated and WML volume was assessed by manual segmentation with automated delineating of different regions. Gait was assessed quantitatively with an electronic walkway as well as the semiquantitatively Tinetti and Timed-Up-and-Go test. RESULTS: WMLs and lacunar infarcts were both independently associated with most gait parameters with stride length as the most sensitive parameter related to WMLs. WMLs in the sublobar (basal ganglia/internal capsule) and limbic areas and lacunar infarcts in the frontal lobe and thalamus were related to a lower velocity. CONCLUSIONS: Cerebral small vessel disease is related to gait disturbances. Because small vessel disease may, in part, be preventable, it should be regarded as a potentially important target for postponing gait impairment.

Hypertension and cerebral diffusion tensor imaging in small vessel disease.

BACKGROUND AND PURPOSE: Hypertension is a risk factor for cerebral small vessel disease, which includes white matter lesions (WML) and lacunar infarcts. These lesions are frequently observed on MRI scans of elderly people and play a role in cognitive decline. Preferably, one would like to evaluate the effect of hypertension before fluid-attenuated inversion recovery visible macrostructural lesions occur, possibly by investigating its effect on the microstructural integrity of the white matter. Diffusion tensor imaging provides measures of structural integrity. METHODS: In 503 patients with small vessel disease, aged between 50 and 85 years, we cross-sectionally studied the relation between blood pressure, hypertension, and hypertension treatment status and diffusion tensor imaging parameters in both normal-appearing white matter (NAWM) and WMLs. All of the subjects underwent 1.5-T MRI and diffusion tensor imaging scanning. Fractional anisotropy and mean diffusivity were calculated in both NAWM and WMLs. RESULTS: Increased blood pressure and hypertension were significantly related to lower fractional anisotropy in both NAWM and WMLs and to higher mean diffusivity in WMLs. For hypertensives, odds ratios for the risk of impaired microstructural integrity (fractional anisotropy) were 3.1 (95% CI: 1.8 to 5.7) and 2.1 (95% CI: 1.2 to 3.5) in NAWM and WMLs, respectively, compared with normotensives. Fractional anisotropy odds ratios for treated uncontrolled subjects were 6.5 (95% CI: 3.3 to 12.7) and 2.7 (95% CI: 1.5 to 5.1) in NAWM and WMLs, respectively, compared with normotensives. CONCLUSIONS: Our data show that diffusion tensor imaging may be an appropriate tool to monitor the effect of blood pressure and the response to treatment on white matter integrity, probably even before the development of WMLs on fluid-attenuated inversion recovery.

Location Sensitive Deep Convolutional Neural Networks for Segmentation of White Matter Hyperintensities.

The anatomical location of imaging features is of crucial importance for accurate diagnosis in many medical tasks. Convolutional neural networks (CNN) have had huge successes in computer vision, but they lack the natural ability to incorporate the anatomical location in their decision making process, hindering success in some medical image analysis tasks. In this paper, to integrate the anatomical location information into the network, we propose several deep CNN architectures that consider multi-scale patches or take explicit location features while training. We apply and compare the proposed architectures for segmentation of white matter hyperintensities in brain MR images on a large dataset. As a result, we observe that the CNNs that incorporate location information substantially outperform a conventional segmentation method with handcrafted features as well as CNNs that do not integrate location information. On a test set of 50 scans, the best configuration of our networks obtained a Dice score of 0.792, compared to 0.805 for an independent human observer. Performance levels of the machine and the independent human observer were not statistically significantly different (p-value = 0.06).

Automated detection of white matter hyperintensities of all sizes in cerebral small vessel disease.

PURPOSE: White matter hyperintensities (WMH) are seen on FLAIR-MRI in several neurological disorders, including multiple sclerosis, dementia, Parkinsonism, stroke and cerebral small vessel disease (SVD). WMHs are often used as biomarkers for prognosis or disease progression in these diseases, and additionally longitudinal quantification of WMHs is used to evaluate therapeutic strategies. Human readers show considerable disagreement and inconsistency on detection of small lesions. A multitude of automated detection algorithms for WMHs exists, but since most of the current automated approaches are tuned to optimize segmentation performance according to Jaccard or Dice scores, smaller WMHs often go undetected in these approaches. In this paper, the authors propose a method to accurately detect all WMHs, large as well as small. METHODS: A two-stage learning approach was used to discriminate WMHs from normal brain tissue. Since small and larger WMHs have quite a different appearance, the authors have trained two probabilistic classifiers: one for the small WMHs (⩽3 mm effective diameter) and one for the larger WMHs (>3 mm in-plane effective diameter). For each size-specific classifier, an Adaboost is trained for five iterations, with random forests as the basic classifier. The feature sets consist of 22 features including intensities, location information, blob detectors, and second order derivatives. The outcomes of the two first-stage classifiers were combined into a single WMH likelihood by a second-stage classifier. Their method was trained and evaluated on a dataset with MRI scans of 362 SVD patients (312 subjects for training and validation annotated by one and 50 for testing annotated by two trained raters). To analyze performance on the separate test set, the authors performed a free-response receiving operating characteristic (FROC) analysis, instead of using segmentation based methods that tend to ignore the contribution of small WMHs. RESULTS: Experimental results based on FROC analysis demonstrated a close performance of the proposed computer aided detection (CAD) system to human readers. While an independent reader had 0.78 sensitivity with 28 false positives per volume on average, their proposed CAD system reaches a sensitivity of 0.73 with the same number of false positives. CONCLUSIONS: The authors have developed a CAD system with all its ingredients being optimized for a better detection of WMHs of all size, which shows performance close to an independent reader.

Accelerated development of cerebral small vessel disease in young stroke patients.

OBJECTIVE: To study the long-term prevalence of small vessel disease after young stroke and to compare this to healthy controls. METHODS: This prospective cohort study comprises 337 patients with an ischemic stroke or TIA, aged 18-50 years, without a history of TIA or stroke. In addition, 90 age- and sex-matched controls were included. At follow-up, lacunes, microbleeds, and white matter hyperintensity (WMH) volume were assessed using MRI. To investigate the relation between risk factors and small vessel disease, logistic and linear regression were used. RESULTS: After mean follow-up of 9.9 (SD 8.1) years, 337 patients were included (227 with an ischemic stroke and 110 with a TIA). Mean age of patients was 49.8 years (SD 10.3) and 45.4% were men; for controls, mean age was 49.4 years (SD 11.9) and 45.6% were men. Compared with controls, patients more often had at least 1 lacune (24.0% vs 4.5%, p < 0.0001). In addition, they had a higher WMH volume (median 1.5 mL [interquartile range (IQR) 0.5-3.7] vs 0.4 mL [IQR 0.0-1.0], p < 0.001). Compared with controls, patients had the same volume WMHs on average 10-20 years earlier. In the patient group, age at stroke (ß = 0.03, 95% confidence interval [CI] 0.02-0.04) hypertension (ß = 0.22, 95% CI 0.04-0.39), and smoking (ß = 0.18, 95% CI 0.01-0.34) at baseline were associated with WMH volume. CONCLUSIONS: Patients with a young stroke have a higher burden of small vessel disease than controls adjusted for confounders. Cerebral aging seems accelerated by 10-20 years in these patients, which may suggest an increased vulnerability to vascular risk factors.

Cerebral small vessel disease and incident parkinsonism: The RUN DMC study.

OBJECTIVE: To investigate the relation between baseline cerebral small vessel disease (SVD) and the risk of incident parkinsonism using different MRI and diffusion tensor imaging (DTI) measures. METHODS: In the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort (RUN DMC) study, a prospective cohort study, 503 elderly participants with SVD and without parkinsonism were included in 2006. During follow-up (2011-2012), parkinsonism was diagnosed according to UK Brain Bank criteria. Cox regression analysis was used to investigate the association between baseline imaging measures and incident all-cause parkinsonism and vascular parkinsonism (VP). Tract-based spatial statistics analysis was used to identify differences in baseline DTI measures of white matter (WM) tracts between participants with VP and without parkinsonism. RESULTS: Follow-up was available from 501 participants (mean age 65.6 years; mean follow-up duration 5.2 years). Parkinsonism developed in 20 participants; 15 were diagnosed with VP. The 5-year risk of (any) parkinsonism was increased for those with a high white matter hyperintensity (WMH) volume (hazard ratio [HR] 1.8 per SD increase, 95% confidence interval [CI] 1.3-2.4) and a high number of lacunes (HR 1.4 per number increase, 95% CI 1.1-1.8) at baseline. For VP, this risk was also increased by the presence of microbleeds (HR 5.7, 95% CI 1.9-16.8) and a low gray matter volume (HR 0.4 per SD increase, 95% CI 0.2-0.8). Lower fractional anisotropy values in bifrontal WM tracts involved in movement control were observed in participants with VP compared to participants without parkinsonism. CONCLUSIONS: SVD at baseline, especially a high WMH volume and a high number of lacunes, is associated with incident parkinsonism. Our findings favor a role of SVD in the etiology of parkinsonism.

Cerebral microbleeds are related to subjective cognitive failures: the RUN DMC study.

Cerebral small vessel disease (SVD), including white matter lesions (WML) and lacunar infarcts, is related to objective cognitive impairment but also to subjective cognitive failures (SCF). SCF have reported to be an early predictor of dementia. Cerebral microbleeds (MB) are another manifestation of SVD and have been related to cognitive impairment, but the role of MB in SCF has never been studied. We therefore investigated whether MB are related to SCF among non-demented elderly individuals with SVD, independent of coexisting WML and lacunar infarcts. The RUN DMC study is a prospective cohort study among 503 older persons with cerebral SVD between 50 and 85 years of age. All participants underwent FLAIR and T2* scanning. SCF, subjective memory failures (SMF), and subjective executive failures (SEF) were assessed. The relation between SCF and the presence, number and location of MB was assessed by linear regression analyses adjusted for age, sex, education, depressive symptoms, cognitive function, total brain volume, normalized hippocampal volume, territorial infarcts, WML, and lacunar infarcts. MB were present in 11%. We found a relation between the presence, total number and lobar located MB, and SCF, SMF, and SEF and the reported progression of these failures, especially in participants with good objective cognitive function. In conclusion, MB are related to SCF independent of co-existing WML and lacunar infarcts, especially in those with good objective cognitive performance. These results suggest that MB are associated with the earliest manifestations of cognitive impairment. MB may help us to understand the role of the ever-expanding spectrum of SVD in cognitive impairment.

Cognitive function in small vessel disease: the additional value of diffusion tensor imaging to conventional magnetic resonance imaging: the RUN DMC study.

The structural integrity of the cerebral white matter, including that of the white matter lesions (WML) and of the surrounding normal appearing white matter (NAWM), can be assessed with diffusion tensor imaging (DTI), which is suggested to be of added value in the explanation of cognitive dysfunction in cerebral small vessel disease (SVD). We investigated the value of DTI of NAWM and WML in addition to conventional magnetic resonance imaging (MRI) parameters in the variance of cognitive performance in subjects with SVD. 499 individuals with SVD, 50-85 years, without dementia, underwent MRI scanning, including a DTI sequence. Grey matter, white matter (WM), and WML volume, number of microbleeds, lacunar and territorial infracts, and mean diffusivity (MD) and fractional anisotropy (FA) in NAWM, WML, and total WM were related to cognitive performance in multivariate regression analyses, after adjustment for age, gender, and education. All MRI parameters together accounted for 1-6% of the variance in cognitive function on top of 22-36% already explained by age, gender, and level of education. Both mean MD and FA of the NAWM, WML, and total WM did not substantially contribute to the explained variance of cognitive function, to that already explained by conventional MRI parameters. When considered separately, the MD of the (NA)WM had the strongest association with cognitive performance. In conclusion, DTI of NAWM and WML has limited additional value to conventional MRI parameters in the etiological explanation of the variance in cognitive function among individuals with SVD.

Diffusion tensor imaging and mild parkinsonian signs in cerebral small vessel disease.

Although the role of cerebral small vessel disease (SVD), including white matter lesions (WMLs) and lacunar infarcts, in mild parkinsonian signs (MPS) is increasingly being recognized, not all individuals with SVD have MPS. Using diffusion tensor imaging (DTI), we investigated whether the presence of MPS was dependent on the microstructural integrity underlying WMLs, the early loss of integrity of the normal-appearing white matter (NAWM) and location of this damage. We examined 483 elderly subjects with SVD and without parkinsonism. Subjects with severe loss of integrity within their WMLs had a higher risk of MPS, regardless of WML volume (fractional anisotropy odds ratios = 1.9; 95% confidence interval, 1.1-3.4). The same was found in the normal-appearing white matter, but this association disappeared after adjustment for WMLs and lacunar infarcts. The integrity of the periventricular frontal regions-of-interest was significantly lower in subjects with MPS than without, independent of WMLs and lacunar infarcts. This study indicates that integrity of WMLs, especially in the frontal lobe, is associated with MPS. Diffusion tensor imaging may be of added value in investigating the underlying mechanisms of parkinsonian signs in subjects with SVD.