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.

Structural network connectivity and cognition in cerebral small vessel disease.

Cerebral small vessel disease (SVD), including white matter hyperintensities (WMH), lacunes and microbleeds, and brain atrophy, are related to cognitive impairment. However, these magnetic resonance imaging (MRI) markers for SVD do not account for all the clinical variances observed in subjects with SVD. Here, we investigated the relation between conventional MRI markers for SVD, network efficiency and cognitive performance in 436 nondemented elderly with cerebral SVD. We computed a weighted structural connectivity network from the diffusion tensor imaging and deterministic streamlining. We found that SVD-severity (indicated by higher WMH load, number of lacunes and microbleeds, and lower total brain volume) was related to networks with lower density, connection strengths, and network efficiency, and to lower scores on cognitive performance. In multiple regressions models, network efficiency remained significantly associated with cognitive index and psychomotor speed, independent of MRI markers for SVD and mediated the associations between these markers and cognition. This study provides evidence that network (in)efficiency might drive the association between SVD and cognitive performance. This highlights the importance of network analysis in our understanding of SVD-related cognitive impairment in addition to conventional MRI markers for SVD and might provide an useful tool as disease marker.

Relationship between white matter hyperintensities, cortical thickness, and cognition.

BACKGROUND AND PURPOSE: White matter hyperintensities (WMH) are associated with clinically heterogeneous symptoms that cannot be explained by these lesions alone. It is hypothesized that these lesions are associated with distant cortical atrophy and cortical thickness network measures, which can result in an additional cognitive impairment. Here, we investigated the relationships between WMH, cortical thickness, and cognition in subjects with cerebral small vessel disease. METHODS: A total of 426 subjects with cerebral small vessel disease were included, aged between 50 and 85 years, without dementia, and underwent MRI scanning. Cortical thickness analysis was performed, and WMH were manually segmented. Graph theory was applied to examine the relationship between network measures and WMH, and structural covariance matrices were constructed using inter-regional cortical thickness correlations. RESULTS: Higher WMH load was related to lower cortical thickness in frontotemporal regions, whereas in paracentral regions, this was related to higher cortical thickness. Network analyses revealed that measures of network disruption were associated with WMH and cognitive performance. Furthermore, WMH in specific white matter tracts were related to regional-specific cortical thickness and network measures. Cognitive performances were related to cortical thickness in frontotemporal regions and network measures, and not to WMH, while controlling for cortical thickness. CONCLUSIONS: These cross-sectional results suggest that cortical changes (regional-specific damage and network breakdown), mediated (in)directly by WMH (tract-specific damage) and other factors (eg, vascular risk factors), might lead to cognitive decline. These findings have implications in understanding the relationship between WMH, cortical morphology, and the possible attendant cognitive decline and eventually dementia.

White matter integrity and depressive symptoms in cerebral small vessel disease: The RUN DMC study.

OBJECTIVE: Depressive symptoms are common in elderly with cerebral small vessel disease (SVD). As not every individual with SVD experiences depressive symptoms, other factors might play a role. We therefore investigated the white matter (WM) integrity of the white matter tracts in elderly with depressive symptoms, independent of global cognitive function, by applying the tract-based spatial statistics (TBSS). DESIGN: Prospective cohort study with cross-sectional baseline data. SETTING: Radboud University Nijmegen Medical Centre, The Netherlands. PARTICIPANTS: 438 individuals aged between 50-85 years, with SVD without dementia. MEASUREMENTS: Diffusion tensor imaging parameters and depressive symptoms, assessed with the Center for Epidemiologic Studies Depression Scale. RESULTS: Compared with non-depressed participants (N = 287), those with depressive symptoms (N = 151) had lower fractional anisotropy in the genu and body of the corpus callosum, bilateral inferior fronto-occipital fasciculus, uncinate fasciculus, and corona radiata. These differences disappeared after adjustment for white matter hyperintensities (WMH) and lacunar infarcts. Mean-, axial- and radial diffusivity were higher in these areas in participants with depressive symptoms. After additional adjustment for WMH and lacunar infarcts, the changes observed in radial diffusivity also disappeared. Adding global cognition as confounding variable altered the diffusion parameters only slightly. CONCLUSION: This study indicates that elderly with depressive symptoms show a lower WM integrity, independent of global cognitive function, and that the presence of SVD is mostly responsible, affecting the fronto-subcortical regions and hereby disrupting the neural circuitry involved in mood regulation.

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.

Dementia: Alzheimer pathology and vascular factors: from mutually exclusive to interaction.

Alzheimer's disease (AD) is the most common type of dementia. Both its incidence and prevalence are expected to increase exponentially as populations' age worldwide. Despite impressive efforts of research worldwide, neither cure nor effective preventive strategy is available for this devastating disease. Currently there are several hypotheses on what causes AD, with the amyloid hypothesis being the most investigated and accepted hypothesis over the past 20 years. However the exact role of amyloid-ß in the onset and progression of AD is not yet fully understood, and even the validity of the amyloid hypothesis itself is still being discussed. This debate is fuelled by the vascular hypothesis, as increasing epidemiological, neuroimaging, pathological, pharmacotherapeutic and clinical studies suggest that vascular pathology plays a key role in the onset and progression of AD. We here will discuss arguments in favor and limitations of both hypotheses within the framework of available literature, but also provide arguments for convergence of both hypotheses. Finally we propose approaches that may aid in unraveling the etiology and treatment of AD. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.

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.

[Cerebral arterial air embolism: the effect of hyperbaric oxygen therapy]. / Cerebrale arteriële luchtembolie.

BACKGROUND: Iatrogenic gas embolism is the presence of gas in vascular structures. Feared are those in coronary or cerebral arteries. These can result in cerebral or myocardial infarction. CASE DESCRIPTION: A 79-year-old female underwent CT-guided biopsy of the lung. Minutes later she developed neurological symptoms. After administration of oxygen her symptoms initially improved, but later worsened. Based on her symptoms air embolism was suspected. She recovered fully after treatment with hyperbaric oxygen. CONCLUSION: Air embolism is a potentially life-threatening complication of surgical, radiological or vascular interventions. Early recognition can lead to prompt treatment and better prognosis. If air embolism is suspected the patient should be treated according to ABCDE principles and oxygen should be administered. In case of neurological or circulatory symptoms a hospital that could provide hyperbaric oxygen therapy should be contacted as soon as possible.

Prognostic Value of Histopathological Thrombus Age in Large Vessel Occlusion-Related Stroke.

INTRODUCTION: Acute mechanical thrombectomy (MT) is the preferred treatment for large vessel occlusion-related stroke. Histopathological research on the obtained occlusive embolic thrombus may provide information regarding the aetiology and pathology of the lesion to predict prognosis and propose possible future acute ischaemic stroke therapy. METHODS: A total of 75 consecutive patients who presented to the Amphia Hospital with acute large vessel occlusion-related stroke and underwent MT were included in the study. The obtained thrombus materials were subjected to standard histopathological examination. Based on histological criteria, they were considered fresh (<1 day old) or old (>1 day old). Patients were followed for 2 years for documentation of all-cause mortality. RESULTS: Thrombi were classified as fresh in 40 patients (53%) and as older in 35 patients (47%). Univariate Cox regression analysis showed that thrombus age, National Institutes of Health Stroke Scale at hospital admission, and patient age were associated with long-term mortality (p < 0.1). Multivariable Cox hazards and Kaplan-Meier analysis demonstrated that after extensive adjustment for clinical and procedural variables, thrombus age persisted in being independently associated with higher long-term mortality (hazard ratio: 3.34; p = 0.038, log-rank p = 0.013). CONCLUSION: In this study, older thromboemboli are responsible for almost half of acute large ischaemic strokes. Moreover, the presence of an old thrombus is an independent predictor of mortality in acute large vessel occlusion-related stroke. More research is warranted regarding future therapies based on thrombus composition.

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.

Cortical thickness is associated with gait disturbances in cerebral small vessel disease.

Although gait disturbances are present in a substantial portion of patients with cerebral small vessel disease (SVD), their pathogenesis has not been clarified as they are not entirely explained by the white matter lesions (WMLs) and lacunar infarcts. The role of cortical thickness in these patients remains largely unknown. We aimed to assess the regions of cortical thickness associated with distinct gait parameters in patients with SVD, and whether these associations were dependent on WMLs and lacunar infarcts. MRI data were obtained from 415 subjects with SVD, aged between 50 and 85 years. We assessed cortical thickness using surface-based cortical thickness analysis, and gait performance using the GAITRite system. Cortical thickness of predominantly the orbitofrontal and ventrolateral prefrontal cortex, the inferior parietal lobe, cingulate areas and visual association cortices was positively related to stride length. Thickness of the primary and supplementary motor cortices and the cingulate cortex was positively related to cadence, while thickness of the orbitofrontal and ventrolateral prefrontal cortex, anterior cingulate cortex and especially the inferior parietal lobe and superior temporal gyrus was negatively related to stride width. The associations with stride length and width were partially explained by the subcortical WMLs and lacunar infarcts. Cortical thickness may therefore be important in gait disturbances in individuals with SVD, with different cortical patterns for specific gait parameters. We suggest that cortical atrophy is part of the disease processes in patients with SVD.

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.

Loss of white matter integrity is associated with gait disorders in cerebral small vessel disease.

Gait disturbances are common in the elderly. Cerebral small vessel disease, including white matter lesions and lacunars infarcts, is thought to disrupt white matter tracts that connect important motor regions, hence resulting in gait disturbances. Pathological studies have demonstrated abnormalities in white matter that may appear normal on brain imaging. The loss of integrity in such normal-appearing white matter may partly be due to small vessel disease and may play a role in causing gait disturbances. The white matter regions involved in these gait disturbances, both in white matter lesions and normal-appearing white matter, remain unclear. We, therefore, aimed to investigate the relation between the location of white matter lesions and gait using voxel-based morphometry analysis, as well as between white matter integrity and gait by applying tract-based spatial statistics to diffusion tensor imaging parameters. Magnetic resonance imaging was carried out on 429 individuals in the age range of 50 and 85 years, with cerebral small vessel disease without dementia or parkinsonism. Gait was assessed quantitatively. White matter lesions, especially in the centrum semiovale and periventricular frontal lobe, were related to a lower gait velocity, shorter stride length and broader stride width. Loss of white matter integrity, as indicated by a lower fractional anisotropy and higher mean diffusivity, in numerous regions was related to a lower gait performance. Most of these regions were located in the normal-appearing white matter. The strongest significant association was found in the corpus callosum, particularly the genu. Most of the associations in the normal-appearing white matter disappeared after controlling for white matter lesions and lacunar infarcts, except for some in the corpus callosum. In conclusion, our study showed that using a combination of voxel-based morphometry analysis of the white matter lesions and diffusion tensor imaging is of added value in investigating the pathophysiology of gait disturbances in subjects with small vessel disease. Our data demonstrate that, in elderly subjects with small vessel disease, widespread disruption of white matter integrity, predominantly in the normal-appearing white matter, is involved in gait disturbances. In particular, loss of fibres interconnecting bilateral cortical regions, especially the prefrontal cortex that is involved in cognitive control on motor performance, may be important. The most important mechanisms underlying affected normal-appearing white matter are probably a direct effect of small vessel disease or, indirectly, remote effects of white matter lesions and lacunar infarcts.

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.

Frontal and temporal microbleeds are related to cognitive function: the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort (RUN DMC) Study.

BACKGROUND AND PURPOSE: Cerebral small vessel disease, including white matter lesions and lacunar infarcts, is related to cognitive impairment. Cerebral microbleeds (MBs) are increasingly being recognized as another manifestation of small vessel disease and are also related to cognitive function. However, it remains unclear whether this relation is independent of white matter lesions and lacunar infarcts and if location of MB plays a role. We investigated the relation between the presence, number, and location of MB and cognitive performance adjusted for white matter lesions and lacunar infarcts. METHODS: Presence, number, and location of MB were rated on a gradient echo T2*-weighted MRI in 500 nondemented elderly patients with small vessel disease. Cognitive performance was assessed in different domains. Analyses were adjusted for age, sex, education, depressive symptoms, total brain volume, white matter lesion volume, and lacunar and territorial infarcts. RESULTS: Mean age was 65.6 years (SD 8.8) and 57% were male. MBs were present in 10.4% of the participants. Subjects with MBs were significantly older, had a higher white matter lesion volume, and more lacunar infarcts (P<0.001). Presence and number of MBs were related to global cognitive function (ß-0.10, P=0.008; ß-0.20, P=0.002), psychomotor speed (ß-0.10, P=0.012; ß-0.19, P=0.006), and attention (ß-0.10, P=0.02; ß-0.205, P=0.001). The relations with cognitive performance were mainly driven by frontal, temporal, and strictly deep located MB. CONCLUSIONS: Frontal and temporal located MBs correlate with cognitive performance in nondemented elderly patients independent of coexisting other small vessel disease-related lesions. MBs are clinically not silent and may help to understand the role of vascular disease in cognitive decline.

Microbleeds are independently related to gait disturbances in elderly individuals with cerebral small vessel disease.

BACKGROUND AND PURPOSE: Cerebral small vessel disease (SVD), including white matter lesions and lacunar infarcts, is related to gait disturbances. Microbleeds (MB) are another manifestation of SVD, but their clinical impact remains unclear. We therefore investigated the relation between the number and location of MB and gait, independently of white matter lesions and lacunar infarcts. METHODS: MRI scanning was performed in 485 nondemented elderly individuals with cerebral SVD. The number and location of MB were rated. Gait was assessed with a GAITRite system and the Tinetti and Timed-Up-and-Go tests. MB were related to gait parameters by age, height, total brain volume, white matter lesions, and number of lacunar infarcts-adjusted linear regression. RESULTS: A higher number of MB was independently related to a shorter stride length and poorer performance on the Tinetti and Timed-Up-and-Go tests. These relations seemed to be explained by MB in the temporal and frontal lobe and basal ganglia, including the thalamus. CONCLUSIONS: This study offers the first indication that MB may be associated with gait disturbances, independently of other coexisting markers of SVD.

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.