Aspects of Subcortical Ischaemic Vascular Disease : Early clinical manifestations and associations with Type 2 diabetes mellitus

Summary Subcortical ischaemic vascular disease (SIVD) is an important cause of cognitive impairment in elderly patients. Screening and diagnostic tests are needed to identify these patients. The HIV dementia scale (HDS) is a reliable and quantitative scale for identifying HIV dementia1. The cognitive profile of HIV dementia has subcortical features that resemble subcortical ischaemic vascular disease (SIVD). The clinical syndrome is characterized by early impairment of attention and executive function, accompanied by a slowing of motor performance and information processing, while memory functions remain relatively intact2. Chapter 2 reported the results of an attempt to validate the HDS for elderly SIVD patients. The primary hypotheses were that the HDS could be used as a screening test in SIVD patients and that it could be used as a screening test for patients who have vascular risk factors. The HDS consists of four items and is easy to administer. All items of the HDS represent characteristics of subcortical cognitive functions, (i.e. psychomotor speed, concentration, executive functions and memory skills). Because the neuropsychological profiles of patients with normal pressure hydrocephalus (NPH) are identical to those of SIVD patients, NPH patients were also included in the study population2,3. The results of the study indicated that the HDS is capable of discriminating between patients with cognitive impairments due to SIVD or a NPH and normal control subjects in an older population. Patients had HDS scores of 5.1 ± 3.5 (maximum score 16), and control subjects had scores of 13.0± 2.4 (p < 0.0001). The results further showed that the HDS is of additional value for subjects whose Mini Mental State Examination (MMSE) scores fall within the normal range. The results of this study suggest that the HDS is capable of detecting cognitive impairment in SIVD patients and may therefore be used in clinical trials in SIVD patients or those who are at risk for SIVD. The central hypothesis of Chapter 3 was that a clinical neurophysiological test could be helpful for detecting cognitive impairment in SIVD patients. The late responses that are elicited by the auditory oddball paradigm are considered to be related to cognitive processing4. It has been shown that the latency of the N2 complex and the P3 is prolonged in patients with Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Binswanger’s disease and depression5-7. Several studies have investigated the auditory oddball paradigm in patients with vascular white matter disease (i.e. leukoaraiosis or lacunar infarcts)6,8-11. These studies, however, used either a definition of cognitive decline that was based on DSM-IV criteria for Alzheimer’s dementia12 or tests of cognitive function that were not described in detail. In addition, these studies analyzed only the P3 wave. We attempted to determine whether the various deflections of the event-related potential (N1, N2 complex and P3) that are evoked by the auditory oddball paradigm could differentiate between patients who have vascular cognitive impairment (VCI) caused by SIVD in an early phase of the disease and age-matched control subjects. We demonstrated that N2 latency was significantly longer in patients with VCI (254.6 ± 25.1 milliseconds) than it was in age-matched control subjects (235 ± 28.6 milliseconds) (p = 0.001), whereas the latencies of P3 and N1 were not significantly different. The peak-to-peak amplitude of the N2 complex to the P3 wave was significantly lower in the patient group (patients 11.5 ± 7.0 microvolt vs. controls 15.4 ± 9.4 microvolt, p = 0.02). White-matter lesions revealed by MRI were not correlated with N2 latency (r = -0.255, p = 0.3). These data show that the latency of the N2 complex is longer and the peak-to-peak amplitude of the N2 to P3 wave is lower for a well-defined group of VCI patients than it is for healthy control subjects. Subcortical ischaemic vascular disease incorporates both white-matter lesions and lacunar infarcts. While hypertension is the most important and consistent risk factor for white-matter lesions and lacunar infarcts, the data on the relation between these lesions and diabetes mellitus (DM) are not consistent. Because of the frequency of both SIVD and DM among elderly subjects we investigated the relation between DM and SIVD. Chapter 4 reports the result of a systematic review addressing the association between DM and structural brain-imaging abnormalities. It is known that DM increases the risk of cerebral large-vessel disease two to threefold. Whether DM is a risk factor for SIVD, including white-matter lesions and lacunar infarcts, remains unclear. Our systematic review addressed available data on brain-imaging changes in diabetic patients, as revealed by computer tomo-graphy (CT) and magnetic resonance imaging (MRI); it also analysed studies that use magnetic resonance spectroscopy (MRS), positron emission tomo-graphy (PET) and single-photon emission computer tomography (SPECT) to investigate the relationship between DM and abnormalities. We also assessed the relationship of these cerebral changes to cognition, and related disease variables, including DM subtype, age and hypertension, DM duration, medi-ation use and glycaemic control. Eligible studies were evaluated according to predefined inclusion criteria (i.e. clear imaging-outcome measures, a clear definition of DM and a sample size of at least 20 DM patients). Data on study design, DM type, treatment and associated comorbidity, imaging modality (MRI, MRS, CT, SPECT or PET) and imaging findings were extracted from the fifty-five articles that were included in the review. The methodology of these studies with regard to population selection, DM assessment, neuro-imaging rating methods and data analyses were heterogeneous. DM was associated with cerebral atrophy in eight out of ten studies that investigated this relationship. Eight of nineteen studies reported an association between DM and lacunar infarcts. We found little evidence of an association with white-matter lesions. Studies that used PET and SPECT reported regional abnormalities of cerebral blood flow and cerebral glucose metabolism. None of the studies assessed the relationship between imaging findings and cognition. Data on the relationship between imaging findings and disease variables (e.g. age, hypertension, medication use, glycaemic control) were scarce as well. We concluded that DM is associated with cerebral atrophy and lacunar infarcts, but that the association with white-matter lesions is equivocal. Chapter 5 elaborated on the conclusions that were drawn in Chapter 4 by reporting results from a cross-sectional study that compared a well-defined population of independently living elderly patients with Type 2 DM to healthy control subjects in order to investigate the association between DM, white-matter lesions, lacunar infarcts and brain atrophy. We also compared DM patients who had hypertension to those who did not, in order to determine whether concomitant hypertension could be defined as a relevant disease variable in DM patients. In addition, we investigated the relationship of DM to other disease determinants. The study population consisted of forty-five patients who suffered from Type 2 DM without hypertension (mean age 73.2 ± 5.1 years, mean duration of DM 16.7 ± 11.4 years), forty-five patients with type 2 DM and hypertension (mean age 73.3 ± 5.9 years, mean duration of DM 11.3 ± 9.1 years) and forty-four control subjects (mean age 73.0 ± 5.3 years). All patients and control subjects underwent MRI brain scans. White-matter lesions (WML), cerebral atrophy and medial temporal lobe atrophy (MTA) were rated using a standardized visual rating scale. WML occurred more frequently among DM patients (both with hypertension and without hypertension) than it did among healthy control subjects. Significantly more DWML (deep white-matter lesions) were found among DM patients (with and without hypertension) than were found among control subjects, although no difference was found in the occurrence of periventricular hyperintensities (PVH). Although higher atrophy scores were seen among DM patients than among control subjects, this result was not significant. The association between Type 2 DM and DWML is supported by significant positive correlations between the severity of DWML and the value of glycolysated haemoglobin (HbA1c) and the duration of DM. Data from this cross-sectional study suggest that Type 2 DM is an independent risk factor for DWML in independently living elderly patients. Chapter 6 addressed the detailed neuropsychological profiles of independently functioning patients who have Type 2 DM. It also examined correlations between cognitive impairment and brain lesions (i.e. SIVD, atrophy and lacunar infarcts) that were revealed by MRI. The chapter discusses the influence of relevant disease variables. After adjusting for hypertension neuro-psychological scores for each cognitive domain except for memory functions were worse for a group of elderly patients with Type 2 DM than they were for healthy control subjects. Periventricular hyperintensities (PVH) were an inde-pendent predictor of motor speed, while none of the other MRI measures was independently associated with cognitive impairment. No interactions between the various MRI measures were found. HbA1c and duration of DM were both significantly associated with cognitive dysfunction. Data from this cross-sectional study show that Type 2 DM is associated with diminished cognitive functioning in various cognitive domains, while memory is less affected, after adjusting for hypertension. The association of cognitive impairment with MRI measures is equivocal, although HbA1c and duration of DM were significantly associated with cognitive dysfunction. General discussion Four major conclusions can be drawn from this thesis. First, we demonstrated that the HIV dementia scale (HDS) is a sensitive screening test for detecting cognitive impairment in patients with SIVD, and it may be useful as a screening test for a population of patients who have vascular risk factors. Second, we investigated the auditory oddball paradigm in SIVD patients, showing that the latency of the N2 complex is longer and the peak-to-peak amplitude of the N2 to P3 wave is lower among a well-defined group of VCI patients than among healthy control subjects. Third, Type 2 DM is an indepen-ent risk factor for deep white-matter lesions in independently living elderly patients who visit an outpatient clinic. Fourth, although patients with Type 2 DM exhibit global cognitive deterioration with memory function being less affected after adjustment for hypertension, independent correlations with SIVD or atrophy are equivocal. The concept of SIVD was introduced as a homogeneous subtype of vascular cognitive impairment. This condition is a frequent cause of vascular cognitive impairment, and it is caused by small-vessel disease, which includes cerebral white-matter lesions (WML) and lacunar infarcts in subcortical white and grey matter13-15. Vascular cognitive impairment due to SIVD covers a wide spectrum of cognitive dysfunction, ranging from subtle and clinically often undetected deficits to overt dementia16. The neuropsychological profile is characterized by early impairment of attention and executive function, with a slowing of motor performance and information processing. Episodic memory is believed to be relatively unaffected13. Subtle clinical symptoms are often neglected by physi-cians and both patients and physicians often consider these symptoms as normal signs of ageing. Most screening tests, such as the Mini Mental State Examination (MMSE), are not sensitive enough to detect cognitive impairment in such patients, as they were designed to identify cognitive symptoms, as in Alzheimer’s disease (AD)17. Because of the frequency with which SIVD is identified as a cause of vascular cognitive impairment, a brief and simple cognitive screening test should enable physicians to make early diagnoses and should facilitate the recognition of cognitive problems in patients who are at risk for SIVD. We demonstrated that the HIV dementia scale (HDS) discriminates between elderly patients with subcortical cognitive impairment due to SIVD and normal control subjects. The difference was still significant in a sub-analysis of patients who had MMSE scores of 27 or higher (Chapter 2). Nonetheless, we cannot exclude the possibility that the cognitive deficits in these patients were caused by concomitant AD. Patients with AD present with a different clinical picture, however, and they generally have lower MMSE scores. Our findings suggest that the HDS may be useful as a screening test for SIVD and that it is of additional value for subjects whose MMSE scores fall within the normal range. Second, the auditory oddball paradigm is a neurophysiological method for eliciting an event-related potential (ERP); it contains different deflections with the highest amplitude, usually measured at about 300 milliseconds (P3)4. The late responses elicited by the auditory oddball paradigm are considered related to cognitive processing4. Although several studies have evaluated the diagnostic value of the ERP for patients with dementia, these studies primarily investigated patients with advanced disease, even though early diagnosis is needed to provide adequate care and therapy5-7,18,19. In the present thesis, we showed that the latency of the N2 complex is prolonged and the peak-to-peak amplitude of the N2 complex to P3 wave is lowered in patients who suffer from VCI caused by SIVD (Chapter 3). One of the limitations of this study was that we did not include patients with Alzheimer’s disease. Although Goodin and Aminoff reported that the N1 latency is prolonged in subcortical dementia as compared to cortical dementia, we found no prolonged N1 wave in our patients, as compared to the control subjects20. The patients in the study by Goodin and Aminoff were already suffering from advanced disease, while the patients in our study were clinically characterized by cognitive impairment and not dementia. Further studies are therefore necessary to compare the ERP that it evoked by the auditory oddball paradigm in patients with early Alzheimer’s disease to that which is evoked in patients who suffer from cognitive impairment due to SIVD. We could not demonstrate a significant positive cor-relation between the severity of white-matter abnormalities, the presence of lacunar infarcts and the N2 latency in a subgroup of our study population who underwent MRI. Although this result may be explained by the small sample size, it may also suggest that the functional difference in N2 complex between the two groups is not accompanied by anatomical changes that are revealed by MRI. The lack of correlation is not completely surprising, as the clinical impact of the severity of WML on cognition is also a subject of discussion21. Third, age and hypertension have been shown to be clearly associated with WML on MRI. The association of WML with DM, however, is much weaker than its association with any of the other risk factors. Chapter 4 presented a review of the literature on the association between DM and brain-imaging changes. Studies using CT and MRI provide evidence of a relationship between DM and cerebral atrophy, and they suggest that lacunar infarcts are more common in DM patients, although the association with WML is equivocal. Many of these studies, however, have major methodological limitations, including small sample size, inability to adjust for confounding factors, unclear operationalization of DM and insensitive rating scales for structural brain changes22-26. Because of these inconsistencies and methodological shortcomings, we investigated MRI abnormalities in independently living elderly patients with Type 2 DM who were visiting an outpatient clinic. The results presented in this thesis confirm that Type 2 DM in elderly patients is an independent risk factor for deep WML (Chapter 5). In contrast to other studies, our study population consisted of a well-defined patient group with Type 2 DM, taking comorbid hypertension into account as well. In addition, we used a semi-quantitative rating scale to assess WML; this scale is more sensitive for detecting small amounts of WML than are the rating scales that have been used in many previous studies. Most of the WML scales that have been applied in previous studies were originally developed for patients with cerebrovascular disease or vascular dementia, and they are relatively crude and insensitive. Although these scales discriminates adequately between patients with severe WML and those with modest or subtle abnormalities, they may not be sensitive enough to detect the modest differences in WML that are expected between patients with DM and control subjects (especially in small study populations). Nonetheless, although true volumetric scales claimed higher sensitivity, very few studies have used these techniques27,28. Furthermore, these studies revealed no more WML in DM patients than they did for control subjects. These studies also suffer from other methodological shortcomings (e.g. undefined DM subtype, no adjustment for other disease variables)27,28. Results regarding the association between DM and atrophy are more consistent in the literature23,26,29,30. We also found more atrophy among the DM group, but this difference was not statistically signi-ficant. Although this lack of difference may be due to the visual rating scale that was used, a comparative study between visual rating and volumetry concluded that visual rating is as clinically useful and sometimes even more accurate than volumetry31. Lacunar infarcts occurred sporadically in both DM patients and control subjects. This finding may be attributable to the fact that we investigated independently living patients who were visiting an outpatient clinic in the early phase of vascular disease. Fourth, Type 2 DM is common among the elderly, and it has been associated with cognitive impairment and dementia32-35. Study populations tend to be small, however, and they do not take into account possible differences in educational level. They also do not usually adjust for age, sex and co-morbid hypertension32. In addition, most studies do not include extensive neuropsychological test batteries, and most population studies use global cogni-tive screenings tests, such as the MMSE. We investigated neuropsychological profiles in a well-defined group of elderly patients with Type 2 DM, as well as correlations with brain-imaging abnormalities. In particular, we hypothesized that cognitive impairment in Type 2 DM was caused by SIVD (Chapter 6). When we started our study, the association between cognition and MRI findings in the DM population was not known. We administered an extensive neuropsychological test battery to Type 2 DM patients and investigated associations with MRI lesions, in order to clarify the pathological mechanisms of cognitive impairment among these patients. We demonstrated that global cognitive test scores and neuropsychological scores for each cognitive domain except for memory functions after adjustment for hypertension were worse for a group of independently living elderly patients with Type 2 DM than they were for healthy control subjects. This result has been confirmed by other studies32. Nonetheless, although we have demonstrated that Type 2 DM is an independent risk factor for deep WML, these lesions are not independently associated with cognitive impairment in the diabetic population. Only PVH was an independent predictor for motor speed: none of the other MRI measures was associated with cognitive impairment. Interactions between the various MRI measures were also not present. One of the limitations of this study was that we used a semi-quantitative visual rating scale to assess WML and a visual rating scale to determine atrophy. More sophisticated MRI analyses (e.g. volumetrics) may reveal significant correlations with structural brain changes and cognitive impairment in DM patients. We concluded that the association of cognitive impairment with MRI measures is equivocal in Type 2 DM, but that it may support a dual pathology involving both vascular disease and cerebral atrophy. It is possible that other factors that are not yet known play a role in cognitive impairment in patients with Type 2 DM.Scheltens, P. [Promotor]Weinstein, H. [Copromotor

On the Nonlinearity of Modern Shock-Capturing Schemes

The development is reviewed of shock capturing methods, paying special attention to the increasing nonlinearity in the design of numerical schemes. The nature is studies of this nonlinearity and its relation to upwind differencing is examined. This nonlinearity of the modern shock capturing methods is essential, in the sense that linear analysis is not justified and may lead to wrong conclusions. Examples to demonstrate this point are given

The impact of organisational external peer review on colorectal cancer treatment and survival in the Netherlands

Background: Organisational external peer review was introduced in 1994 in the Netherlands to improve multidisciplinary cancer care. We examined the clinical impact of this programme on colorectal cancer care. Methods: Patients with primary colorectal cancer were included from 23 participating hospitals and 7 controls. Hospitals from the intervention group were dichotomised by their implementation proportion (IP) of the recommendations from each peer review (high IP vs low IP). Outcome measures were the introduction of new multidisciplinary therapies and survival. Results: In total, 45 705 patients were included (1990-2010). Patients from intervention hospitals more frequently received adjuvant chemotherapy for stage III colon cancer. T2-3/M0 rectal cancer patients from hospitals with a high IP had a higher chance of receiving preoperative radiotherapy (OR 1.31, 95% CI 1.11-1.55) compared with the controls and low IP group (OR 0.75, 95% CI 0.63-0.88). There were no differences in the use of preoperative chemoradiation for T4/M0 rectal cancer. Survival was slightly higher in colon cancer patients from intervention hospitals but unrelated to the phase of the programme in which the hospital was at the time of diagnosis. Conclusions: Some positive effects of external peer review on cancer care were found, but the results need to be interpreted cautiously due to the ambiguity of the outcomes and possible confounding factors

Solving One Dimensional Scalar Conservation Laws by Particle Management

We present a meshfree numerical solver for scalar conservation laws in one space dimension. Points representing the solution are moved according to their characteristic velocities. Particle interaction is resolved by purely local particle management. Since no global remeshing is required, shocks stay sharp and propagate at the correct speed, while rarefaction waves are created where appropriate. The method is TVD, entropy decreasing, exactly conservative, and has no numerical dissipation. Difficulties involving transonic points do not occur, however inflection points of the flux function pose a slight challenge, which can be overcome by a special treatment. Away from shocks the method is second order accurate, while shocks are resolved with first order accuracy. A postprocessing step can recover the second order accuracy. The method is compared to CLAWPACK in test cases and is found to yield an increase in accuracy for comparable resolutions.Comment: 15 pages, 6 figures. Submitted to proceedings of the Fourth International Workshop Meshfree Methods for Partial Differential Equation

High Order Upwind Schemes for Multidimensional Magnetohydrodynamics

A general method for constructing high order upwind schemes for multidimensional magnetohydrodynamics (MHD), having as a main built-in condition the divergence-free constraint \divb=0 for the magnetic field vector \bb, is proposed. The suggested procedure is based on {\em consistency} arguments, by taking into account the specific operator structure of MHD equations with respect to the reference Euler equations of gas-dynamics. This approach leads in a natural way to a staggered representation of the \bb field numerical data where the divergence-free condition in the cell-averaged form, corresponding to second order accurate numerical derivatives, is exactly fulfilled. To extend this property to higher order schemes, we then give general prescriptions to satisfy a $(r+1)^{th}$ order accurate \divb=0 relation for any numerical \bb field having a $r^{th}$ order interpolation accuracy. Consistency arguments lead also to a proper formulation of the upwind procedures needed to integrate the induction equations, assuring the exact conservation in time of the divergence-free condition and the related continuity properties for the \bb vector components. As an application, a third order code to simulate multidimensional MHD flows of astrophysical interest is developed using ENO-based reconstruction algorithms. Several test problems to illustrate and validate the proposed approach are finally presented.Comment: 34 pages, including 14 figure

Dispersive wave runup on non-uniform shores

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Evaluation of two strategies to implement physical cancer rehabilitation guidelines for survivors of abdominopelvic cavity tumors:a controlled before-and-after study

PURPOSE: This study evaluates the effectiveness and feasibility of two strategies to implement physical cancer rehabilitation (PCR) guidelines for patients who have survived abdominopelvic cavity malignancies. METHODS: We tested and compared two tailored strategies to implement PCR guidelines for survivors of gastrointestinal, female organ and urogenital organ malignancies, in a clustered controlled before-and-after study. A patient-directed (PD) strategy was tested in five cancer centers, aiming to empower survivors. A multifaceted (MF) strategy was tested in four cancer centers, aiming additionally to influence healthcare professionals and the healthcare organization. Data were collected from existing registration systems, patient questionnaires and professional questionnaires. We measured both implementation- and client outcomes. For insight into the effectiveness we measured indicators related to PCR guidelines: (1) screening with the Distress Thermometer (DT) (=primary outcome measure), (2) information provision concerning physical activity (PA) and physical cancer rehabilitation programs (PCRPs), (3) advice to take part in PA and PCRPs, (4) referral to PCRPs, (5) participation in PCRPs, (6) PA uptake (PAU); and patient reported outcomes (PROs) such as (7) quality of life, (8) fatigue, and (9) empowerment. Furthermore, survivor and center determinants were assessed as possible confounders. Multilevel analyses were performed to compare the scores of the indicators of the PD and MF strategies, as well as the differences between the characteristics of these groups. The use of and experiences with both strategies were measured using questionnaires and Google Analytics to assess feasibility. RESULTS: In total, 1326 survivors participated in the study, 673 in the before- and 653 in the after-measurement. Regarding our primary outcome measure, we found a significant improvement of screening with the DT between the before- and after-measurement for both strategies, respectively from 34.2 to 43.1% (delta=8.9%; odds ratio (OR)=1.6706; p=0.0072) for the PD strategy and from 41.5 to 56.1% (delta=14.6%; OR=1.7098; p=0.0028) for the MF strategy. For both the primary and secondary outcomes, no statistically significant effect of the MF strategy compared to the PD strategy was observed. We found good use of and positive experiences with both strategies. CONCLUSION: Implementation strategies containing tools enhancing patient empowerment seem to be effective in increasing the systematic screening with the DT for survivors of abdominopelvic cavity malignancies. Further research is needed to assess the additional effectiveness of strategies that stimulate compliance among healthcare professionals and healthcare organizations. IMPLICATIONS FOR CANCER SURVIVORS: Using implementation strategies containing tools enhancing patient empowerment seem to be effective in increasing the systematic screening with the DT and might improve the quality of care of patients who have survived abdominopelvic cavity malignancies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11764-021-01045-3

A rarefaction-tracking method for hyperbolic conservation laws

We present a numerical method for scalar conservation laws in one space dimension. The solution is approximated by local similarity solutions. While many commonly used approaches are based on shocks, the presented method uses rarefaction and compression waves. The solution is represented by particles that carry function values and move according to the method of characteristics. Between two neighboring particles, an interpolation is defined by an analytical similarity solution of the conservation law. An interaction of particles represents a collision of characteristics. The resulting shock is resolved by merging particles so that the total area under the function is conserved. The method is variation diminishing, nevertheless, it has no numerical dissipation away from shocks. Although shocks are not explicitly tracked, they can be located accurately. We present numerical examples, and outline specific applications and extensions of the approach.Comment: 21 pages, 7 figures. Similarity 2008 conference proceeding