Karlijn F. de Laat

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 Alzheimers 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 [β = -0.004 (95% confidence interval -0.007 to 0.000; P = 0.03) and β = 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.

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 (&bgr;−0.10, P=0.008; &bgr;−0.20, P=0.002), psychomotor speed (&bgr;−0.10, P=0.012; &bgr;−0.19, P=0.006), and attention (&bgr;−0.10, P=0.02; &bgr;−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.

Causes and consequences of cerebral small vessel disease. The RUN DMC study: a prospective cohort study. Study rationale and protocol

BackgroundCerebral small vessel disease (SVD) is a frequent finding on CT and MRI scans of elderly people and is related to vascular risk factors and cognitive and motor impairment, ultimately leading to dementia or parkinsonism in some. In general, the relations are weak, and not all subjects with SVD become demented or get parkinsonism. This might be explained by the diversity of underlying pathology of both white matter lesions (WML) and the normal appearing white matter (NAWM). Both cannot be properly appreciated with conventional MRI. Diffusion tensor imaging (DTI) provides alternative information on microstructural white matter integrity. The association between SVD, its microstructural integrity, and incident dementia and parkinsonism has never been investigated.Methods/DesignThe RUN DMC study is a prospective cohort study on the risk factors and cognitive and motor consequences of brain changes among 503 non-demented elderly, aged between 50-85 years, with cerebral SVD. First follow up is being prepared for July 2011. Participants alive will be included and invited to the research centre to undergo a structured questionnaire on demographics and vascular risk factors, and a cognitive, and motor, assessment, followed by a MRI protocol including conventional MRI, DTI and resting state fMRI.DiscussionThe follow up of the RUN DMC study has the potential to further unravel the causes and possibly better predict the consequences of changes in white matter integrity in elderly with SVD by using relatively new imaging techniques. When proven, these changes might function as a surrogate endpoint for cognitive and motor function in future therapeutic trials. Our data could furthermore provide a better understanding of the pathophysiology of cognitive and motor disturbances in elderly with SVD. The execution and completion of the follow up of our study might ultimately unravel the role of SVD on the microstructural integrity of the white matter in the transition from normal aging to cognitive and motor decline and impairment and eventually to incident dementia and parkinsonism.

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.

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.

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

BACKGROUNDnCerebral 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.nnnMETHODSnThe 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.nnnRESULTSnInverse relations were found between MD in the WML and NAWM and global cognitive function (β=-.11, p<0.05; β=-.18, p<0.001), psychomotor speed (β=-.15, p<0.01; β=-.18, p<0.001), concept shifting (β=-.11, p<0.05; β=-.10, p<0.05) and attention (β=-.12, p<0.05; β=-.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.nnnCONCLUSIONnDTI 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.

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.

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.

Parkinson disease and comorbid cerebrovascular disease

Optimal management of chronic diseases not only requires tackling of the primary disease processes, but also necessitates timely recognition and treatment of comorbid conditions. In this article, we illustrate this two-pronged approach for two common age-related disorders: Parkinson disease (PD) and cerebrovascular disease (CVD). We first discuss the pathophysiological mechanisms that could provide a link between PD and CVD. Patients with PD have a series of risk factors that could promote development of CVD, but also have several protective factors. We then review the available clinical, radiological and neuropathological evidence to support an association between these two conditions. We conclude by discussing the potential implications for clinical practice, highlighting how comorbid CVD could alter the clinical presentation of PD and reviewing the possibilities for prevention and secondary prophylaxis. Additional research will be needed to fully evaluate the prevalence and clinical relevance of comorbid CVD in PD. Pending further evidence, we recommend that cerebral neuroimaging should be considered if patients with initially uncomplicated PD develop—either acutely or chronically—prominent and/or treatment-resistant gait impairment, postural instability, depression, cognitive decline, or urinary incontinence. Finding comorbid CVD in such patients could have prognostic implications, and could necessitate treatment to arrest further progression of CVD.