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4. Histopathology of diffusion-weighted imaging-positive lesions in cerebral amyloid angiopathy

Author

Telgte, A. ter, Scherlek, A.A., Reijmer, Y.D., Kouwe, A.J. van der, Harten, T. van, Duering, M., Bacskai, B.J., Leeuw, F.E. de, Frosch, M.P., Greenberg, S.M., Veluw, S.J. van, Telgte, A. ter, Scherlek, A.A., Reijmer, Y.D., Kouwe, A.J. van der, Harten, T. van, Duering, M., Bacskai, B.J., Leeuw, F.E. de, Frosch, M.P., Greenberg, S.M., and Veluw, S.J. van

Abstract

Contains fulltext : 220659.pdf (Publisher’s version ) (Closed access), Small subclinical hyperintense lesions are frequently encountered on brain diffusion-weighted imaging (DWI) scans of patients with cerebral amyloid angiopathy (CAA). Interpretation of these DWI+ lesions, however, has been limited by absence of histopathological examination. We aimed to determine whether DWI+ lesions represent acute microinfarcts on histopathology in brains with advanced CAA, using a combined in vivo MRI-ex vivo MRI-histopathology approach. We first investigated the histopathology of a punctate cortical DWI+ lesion observed on clinical in vivo MRI 7 days prior to death in a CAA case. Subsequently, we assessed the use of ex vivo DWI to identify similar punctate cortical lesions post-mortem. Intact formalin-fixed hemispheres of 12 consecutive cases with CAA and three non-CAA controls were subjected to high-resolution 3 T ex vivo DWI and T2 imaging. Small cortical lesions were classified as either DWI+/T2+ or DWI-/T2+. A representative subset of lesions from three CAA cases was selected for detailed histopathological examination. The DWI+ lesion observed on in vivo MRI could be matched to an area with evidence of recent ischemia on histopathology. Ex vivo MRI of the intact hemispheres revealed a total of 130 DWI+/T2+ lesions in 10/12 CAA cases, but none in controls (p = 0.022). DWI+/T2+ lesions examined histopathologically proved to be acute microinfarcts (classification accuracy 100%), characterized by presence of eosinophilic neurons on hematoxylin and eosin and absence of reactive astrocytes on glial fibrillary acidic protein-stained sections. In conclusion, we suggest that small DWI+ lesions in CAA represent acute microinfarcts. Furthermore, our findings support the use of ex vivo DWI as a method to detect acute microinfarcts post-mortem, which may benefit future histopathological investigations on the etiology of microinfarcts.

Published
2020

5. Parietal Involvement in Constructional Apraxia as Measured Using the Pentagon Copying Task

Author

Stigchel, S. (Stefan) van der, Bresser, J. (Jeroen) de, Heinen, R. (Rutger), Koek, H.L. (Huiberdina L.), Reijmer, Y.D. (Yael), Biessels, G.J. (Geert Jan), Berg, E. (Esther) van den, Stigchel, S. (Stefan) van der, Bresser, J. (Jeroen) de, Heinen, R. (Rutger), Koek, H.L. (Huiberdina L.), Reijmer, Y.D. (Yael), Biessels, G.J. (Geert Jan), and Berg, E. (Esther) van den

Abstract

Deficits in copying ("constructional apraxia") is generally defined as a multifaceted deficit. The exact neural correlates of the different types of copying errors are unknown. To assess whether the different categories of errors on the pentagon drawing relate to different neural correlates, we examined the pentagon drawings of the MMSE in persons with subjective cognitive complaints, mild cognitive impairment, or early dementia due to Alzheimer's disease. We adopted a qualitative scoring method for the pentagon copy test (QSPT) which categorizes different possible errors in copying rather than the dichotomous categories "correct" or "incorrect." We correlated (regional) gray matter volumes with performance on the different categories of the QSPT. Results showed that the total score of the QSPT was specifically associated with parietal gray matter volume and not with frontal, temporal, and occipital gray matter volume. A more fine-grained analysis of the errors reveals that the intersection score and the number of angles share their underlying neural correlates and are associated with specific subregions of the parietal cortex. These results are in line with the idea that constructional apraxia can be attributed to the failure to integrate visual information correctly from one fixation to the next, a process called spatial remapping.

Published
2018
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7. Vascular retinopathy in relation to cognitive functioning in an older population--the Hoorn Study

Author

Heringa, S.M., Walraven, I., Moll, A.C., van den Berg, E., Nijpels, G., Stehouwer, C.D., Reijmer, Y.D., Kappelle, L.J., Dekker, J., Biessels, G.J., Experimental Psychology (onderzoeksprogramma PF), Helmholtz Institute, Leerstoel Postma, and Afd Psychologische functieleer

Subjects
Econometric and Statistical Methods: General, International (English), Geneeskunde (GENK), Bescherming en bevordering van de menselijke gezondheid, Geneeskunde(GENK), Medical sciences
Abstract

To the Editor: Cognitive impairment and dementia are important health problems that may be caused by vascular damage in the brain.[1] The cerebral vasculature is anatomically, embryologically, and physiologically related to that of the retina, and both are sensitive to exposure to vascular risk factors.[2, 3] Vascular damage to the retina is easy to measure noninvasively. Hence, visualization of retinal vessels may offer insight into the status of the vessels in the brain and thus provide insight into vascular causes of late-life cognitive impairment. A recent systematic review found variable associations between retinal vascular changes and performance on various cognitive domains in persons without dementia.[4, 5] The goal of the current study was to extend these findings by assessing these associations in a population-based cohort using a detailed neuropsychological examination.

Published
2014

8. Hippocampal disconnection in early Alzheimer's disease: a 7 tesla MRI study

Author

Wisse, L.E., Reijmer, Y.D., Telgte, A. ter, Kuijf, H.J., Leemans, A., Luijten, P.R., Koek, H.L., Geerlings, M.I., Biessels, G.J., Wisse, L.E., Reijmer, Y.D., Telgte, A. ter, Kuijf, H.J., Leemans, A., Luijten, P.R., Koek, H.L., Geerlings, M.I., and Biessels, G.J.

Abstract

Item does not contain fulltext, BACKGROUND: In patients with Alzheimer's disease (AD), atrophy of the entorhinal cortex (ERC) and hippocampal formation may induce degeneration of connecting white matter tracts. OBJECTIVE: We examined the association of hippocampal subfield and ERC atrophy at 7 tesla MRI with fornix and parahippocampal cingulum (PHC) microstructure in patients with early AD. METHODS: Twenty-five patients with amnestic mild cognitive impairment (aMCI) (n = 15) or early AD (n = 10) and 17 controls underwent 3 tesla diffusion MRI to obtain fractional anisotropy (FA) of the fornix and PHC and 7 tesla MRI to obtain ERC and hippocampal subfield volumes. Linear regression analyses were performed, adjusted for age, gender, and intracranial volume. RESULTS: Fornix FA was significantly lower and subiculum, cornu ammonis (CA) 1, and dentate gyrus &CA4 volume were significantly smaller in patients with MCI or AD as compared to controls. In patients with MCI or AD, fornix FA was positively associated with subiculum volume (beta = 0.53, 95% CI 0.10; 0.96), but not with ERC/other subfield volumes. PHC FA was not associated with ERC/subfield volumes. CONCLUSION: These findings indicate that in early AD subiculum atrophy is associated with lower FA of the fornix, which primarily consists of axons originating in the subiculum. This suggests that degeneration of subicular cell bodies and their axons are related processes in early AD.

Published
2015

9. Global brain atrophy but not hippocampal atrophy is related to type 2 diabetes

Author

Wisse, L.E., Bresser, J. de, Geerlings, M.I., Reijmer, Y.D., Portegies, M.L., Brundel, M., Kappelle, L.J., Graaf, Y. van der, Biessels, G.J., and Kessels, R.P.C.

Subjects
Male, medicine.medical_specialty, Alzheimer`s disease Donders Center for Medical Neuroscience [Radboudumc 1], endocrine system diseases, Urology, Hippocampus, Type 2 diabetes, Fluid-attenuated inversion recovery, Hippocampal formation, Neuropsychological Tests, Atrophy, Global brain atrophy, medicine, Humans, Aged, Memory Disorders, Vascular disease, nutritional and metabolic diseases, Brain, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Neurology, Diabetes Mellitus, Type 2, Case-Control Studies, Brain size, Linear Models, Female, Neurology (clinical), Psychology, Cognition Disorders, Neuroscience
Abstract

Aims It has been suggested that in patients with type 2 diabetes mellitus (T2DM), brain atrophy is most pronounced in the hippocampus, but this has not been investigated systematically. The present pooled analysis of three studies examined if hippocampal atrophy is more prominent than global brain atrophy in patients with T2DM relative to controls. Methods Data were derived from a cohort study of patients with vascular disease (SMART-Medea (T2DM = 120; no T2DM = 502)), and from two case–control studies (UDES1 (T2DM = 61; controls = 30) and UDES2 (T2DM = 54; controls = 53)). In SMART-Medea and UDES1, hippocampal volume was obtained by manual tracing on 1.5 Tesla (T) MRI scans. Total brain and intracranial volume (ICV) were determined by an automated segmentation method. In UDES2, hippocampal and total brain volume were determined by FreeSurfer and ICV by manual segmentation on 3 T MRI scans. Results The pooled analyses, adjusted for age and sex, showed a significant negative relation between T2DM and total brain-to-ICV ratio (standardized mean difference = − 1.24%, 95% CI: − 1.63; − 0.86), but not between T2DM and hippocampal-to-ICV ratio (0.00%, 95% CI: − 0.01; 0.00) or between T2DM and hippocampal-to-total brain volume ratio (0.01%, 95% CI: − 0.01; 0.02). In patients with T2DM no associations were found between brain volume measures and HbA1c or memory. Conclusion Patients with T2DM had greater brain atrophy but not hippocampal atrophy, compared to controls. These findings do not support specific vulnerability of the hippocampus in patients with T2DM.

Published
2013

10. Vascular Cognitive Impairment: risk factors and brain MRI correlates

Author

Reijmer, Y.D., Kappelle, L.J., Biessels, Geert Jan, Van den Berg, E., and University Utrecht

Subjects
Econometric and Statistical Methods: General, Bescherming en bevordering van de menselijke gezondheid, Geneeskunde(GENK), Medical sciences, General [Econometric and Statistical Methods]
Abstract

Vascular disease plays an important role in the development of dementia, also in patients diagnosed with Alzheimer’s disease. Risk factors such as hypertension, obesity, and type 2 diabetes, are associated with a two-fold increased risk of cognitive dysfunction and dementia. The development of cognitive impairment due to vascular disease is potentially preventable if patients are recognized and treated early. The present thesis gives more insight in the early stages of cognitive impairment in the context of vascular disease by examining 1) the development of cognitive decline, 2) the relation between vascular risk factors and late-life cognitive dysfunction, and 3) cerebral white matter correlates of cognitive dysfunction in people at risk of vascular disease. The studies in the first part of the thesis were conducted in patients with type 2 diabetes. We show that the development of cognitive decline in the majority of patients with diabetes develops slowly over time, over the course of years. However, we identified a subgroup of patients with accelerated cognitive decline, which seems to be triggered by the progression of both vascular brain lesions and a loss of brain volume on MRI. In the second part of the thesis we evaluated the time-course of vascular risk factors over 15 years in relation to late-life cognitive functioning in a large population-based cohort. We showed that late-life cognitive impairment (~70 years) was most strongly related to the presence of hypertension, adiposity, and hyperglycemia 15-20 years earlier. This indicates that long-term exposure to vascular risk factors, starting at midlife, is harmful to the brain, probably through the slow accumulation of vascular brain damage over the course of decades. Furthermore, we were also able to predict late-life cognitive impairment based on the vascular risk factor profile at midlife. This relation was independent of age and education, which supports the notion that vascular risk factor play an important role in the development of late-life cognitive dysfunction and dementia. The third part of the thesis focused on brain MRI correlates of cognitive dysfunction in patients with Alzheimer’s disease and type 2 diabetes. We demonstrated that the use of advanced brain imaging techniques: diffusion tensor imaging (DTI) and ‘deconvolution based tractography’ can increase the sensitivity to detect microstructural white matter correlates of memory dysfunction in patients with Alzheimer’s disease. This same technique also proved to be more sensitive than conventional brain imaging techniques to white matter abnormalities in patients with diabetes. These white matter abnormalities were related to reduced memory performance and slowing of information processing speed in patients. These findings suggest that microscopic white matter lesions play an important role in the pathogenesis of cognitive impairment in individuals with vascular disease, by disrupting structural and functional connectivity between brain areas. Our findings contribute to a better understanding of the pathogenesis of vascular-related cognitive impairment and contribute to identify individuals at increased risk of dementia at an early stage. This may help to delay or prevent the development of dementia in the near future

Published
2012

12. Global brain atrophy but not hippocampal atrophy is related to type 2 diabetes

Author

Wisse, L.E., Bresser, J. de, Geerlings, M.I., Reijmer, Y.D., Portegies, M.L., Brundel, M., Kappelle, L.J., Graaf, Y. van der, Biessels, G.J., Kessels, R.P.C., et al., Wisse, L.E., Bresser, J. de, Geerlings, M.I., Reijmer, Y.D., Portegies, M.L., Brundel, M., Kappelle, L.J., Graaf, Y. van der, Biessels, G.J., Kessels, R.P.C., and et al.

Abstract

Item does not contain fulltext, AIMS: It has been suggested that in patients with type 2 diabetes mellitus (T2DM), brain atrophy is most pronounced in the hippocampus, but this has not been investigated systematically. The present pooled analysis of three studies examined if hippocampal atrophy is more prominent than global brain atrophy in patients with T2DM relative to controls. METHODS: Data were derived from a cohort study of patients with vascular disease (SMART-Medea (T2DM=120; no T2DM=502)), and from two case-control studies (UDES1 (T2DM=61; controls=30) and UDES2 (T2DM=54; controls=53)). In SMART-Medea and UDES1, hippocampal volume was obtained by manual tracing on 1.5 Tesla (T) MRI scans. Total brain and intracranial volume (ICV) were determined by an automated segmentation method. In UDES2, hippocampal and total brain volume were determined by FreeSurfer and ICV by manual segmentation on 3 T MRI scans. RESULTS: The pooled analyses, adjusted for age and sex, showed a significant negative relation between T2DM and total brain-to-ICV ratio (standardized mean difference=-1.24%, 95% CI: -1.63; -0.86), but not between T2DM and hippocampal-to-ICV ratio (0.00%, 95% CI: -0.01; 0.00) or between T2DM and hippocampal-to-total brain volume ratio (0.01%, 95% CI: -0.01; 0.02). In patients with T2DM no associations were found between brain volume measures and HbA1c or memory. CONCLUSION: Patients with T2DM had greater brain atrophy but not hippocampal atrophy, compared to controls. These findings do not support specific vulnerability of the hippocampus in patients with T2DM.

Published
2014

13. Vascular retinopathy in relation to cognitive functioning in an older population--the Hoorn Study

Author

Experimental Psychology (onderzoeksprogramma PF), Helmholtz Institute, Leerstoel Postma, Afd Psychologische functieleer, Heringa, S.M., Walraven, I., Moll, A.C., van den Berg, E., Nijpels, G., Stehouwer, C.D., Reijmer, Y.D., Kappelle, L.J., Dekker, J., Biessels, G.J., Experimental Psychology (onderzoeksprogramma PF), Helmholtz Institute, Leerstoel Postma, Afd Psychologische functieleer, Heringa, S.M., Walraven, I., Moll, A.C., van den Berg, E., Nijpels, G., Stehouwer, C.D., Reijmer, Y.D., Kappelle, L.J., Dekker, J., and Biessels, G.J.

Published
2014

14. Markers of low-grade inflammation and endothelial dysfunction are related to reduced information processing speed and executive functioning in an older population - the Hoorn Study

Author

Experimental Psychology (onderzoeksprogramma PF), Helmholtz Institute, Leerstoel Postma, Afd Psychologische functieleer, Heringa, S.M., Van den Berg, E., Reijmer, Y.D., Nijpels, G., Stehouwer, C.D., Schalkwijk, C.G., Teerlink, T., Scheffer, P.G., van den Hurk, K., Kappelle, L.J., Dekker, J., Biessels, G.J., Experimental Psychology (onderzoeksprogramma PF), Helmholtz Institute, Leerstoel Postma, Afd Psychologische functieleer, Heringa, S.M., Van den Berg, E., Reijmer, Y.D., Nijpels, G., Stehouwer, C.D., Schalkwijk, C.G., Teerlink, T., Scheffer, P.G., van den Hurk, K., Kappelle, L.J., Dekker, J., and Biessels, G.J.

Published
2014

18. Accelerated cognitive decline in patients with type 2 diabetes: MRI correlates and risk factors

Author

Reijmer, Y.D., Berg, E. van den, Bresser, J.H.J. de, Kessels, R.P.C., Kappelle, L.J., Algra, A., Biessels, G.J., Reijmer, Y.D., Berg, E. van den, Bresser, J.H.J. de, Kessels, R.P.C., Kappelle, L.J., Algra, A., and Biessels, G.J.

Abstract

Item does not contain fulltext, BACKGROUND: Type 2 diabetes mellitus is associated with an increased risk of cognitive decline and dementia. We examined brain imaging correlates and vascular and metabolic risk factors of accelerated cognitive decline in patients with type 2 diabetes. METHODS: Cognitive functioning and brain volume as well as metabolic and vascular risk factors were assessed twice in 68 patients with no dementia with type 2 diabetes with a 4-year interval. Thirty-eight control participants served as a reference group. Volumetric measurements of the total brain, lateral ventricles and white-matter hyperintensities were performed on 1.5T magnetic resonance imaging scans. A regression-based index score was calculated on the basis of the reference group to assess changes in cognitive performance over time, adjusted for age, sex and estimated intelligence quotient. Brain volumes were compared between patients with and without accelerated cognitive decline. Logistic regression analyses were used to identify baseline risk factors for accelerated cognitive decline within the diabetes group. RESULTS: Accelerated cognitive decline was found in 17 (25%) patients with type 2 diabetes and was associated with a greater increase in ventricular volume [mean difference (95% confidence interval): 0.23% (0.08-0.38); p = 0.003] and white-matter hyperintensities volume [0.16% (0.05-0.27); p = 0.006] over the 4-year period. There were no specific vascular or metabolic risk factors associated with accelerated cognitive decline. CONCLUSIONS: Accelerated cognitive decline in patients with type 2 diabetes was associated with progressive changes on brain magnetic resonance imaging, comprising both vascular damage and global atrophy. Exploration of vascular and metabolic risk factors revealed no specific determinants of accelerated cognitive decline.

Published
2011

19. A 4 year follow-up study of cognitive functioning in patients with type 2 diabetes mellitus

Author

Berg, E. van den, Reijmer, Y.D., Bresser, J.H.J. de, Kessels, R.P.C., Kappelle, L.J., Biessels, G.J., Berg, E. van den, Reijmer, Y.D., Bresser, J.H.J. de, Kessels, R.P.C., Kappelle, L.J., and Biessels, G.J.

Abstract

Contains fulltext : 90777.pdf (publisher's version ) (Open Access), AIMS/HYPOTHESIS: Type 2 diabetes mellitus is associated with moderate decrements in cognitive functioning, mainly in verbal memory, information-processing speed and executive functions. How this cognitive profile evolves over time is uncertain. The present study aims to provide detailed information on the evolution of cognitive decrements in type 2 diabetes over time. METHODS: Sixty-eight patients with type 2 diabetes and 38 controls matched for age, sex and estimated IQ performed an elaborate neuropsychological examination in 2002-2004 and again in 2006-2008, including 11 tasks covering five cognitive domains. Vascular and metabolic determinants were recorded. Data were analysed with repeated measures analysis of variance, including main effects for group, time and the group x time interaction. RESULTS: Patients with type 2 diabetes showed moderate decrements in information-processing speed (mean difference in z scores [95% CI] -0.37 [-0.69, -0.05]) and attention and executive functions (-0.25 [-0.49, -0.01]) compared with controls at both the baseline and the 4 year follow-up examination. After 4 years both groups showed a decline in abstract reasoning (-0.16 [-0.30, -0.02]) and attention and executive functioning (-0.29 [-0.40, -0.17]), but there was no evidence for accelerated cognitive decline in the patients with type 2 diabetes as compared with controls (all p > 0.05). CONCLUSIONS/INTERPRETATION: In non-demented patients with type 2 diabetes, cognitive decrements are moderate in size and cognitive decline over 4 years is largely within the range of what can be viewed in normal ageing. Apparently, diabetes-related cognitive changes develop slowly over a prolonged period of time.

Published
2010

20. MRI correlates of cognitive decline in patients with type 2 diabetes

Author

Reijmer, Y.D., Bresser, J.H.J. de, Berg, E. van den, Jongen, C., Viergever, M.A., Kessels, R.P.C., Kappelle, L.J., Biessels, G.J., Reijmer, Y.D., Bresser, J.H.J. de, Berg, E. van den, Jongen, C., Viergever, M.A., Kessels, R.P.C., Kappelle, L.J., and Biessels, G.J.

Abstract

Item does not contain fulltext

Published
2009

21. DHA and cholesterol containing diets influence Alzheimer-like pathology, cognition and cerebral vasculature in APPswe/PS1dE9 mice.

Author

Hooijmans, C.R., Zee, C.E.E.M. van der, Dederen, P.J.W.C., Brouwer, K.M., Reijmer, Y.D., Groen, T. van, Broersen, L.M., Lutjohann, D., Heerschap, A., Kiliaan, A.J., Hooijmans, C.R., Zee, C.E.E.M. van der, Dederen, P.J.W.C., Brouwer, K.M., Reijmer, Y.D., Groen, T. van, Broersen, L.M., Lutjohann, D., Heerschap, A., and Kiliaan, A.J.

Abstract

Contains fulltext : 79884.pdf (publisher's version ) (Closed access), Cholesterol and docosahexenoic acid (DHA) may affect degenerative processes in Alzheimer's Disease (AD) by influencing Abeta metabolism indirectly via the vasculature. We investigated whether DHA-enriched diets or cholesterol-containing Typical Western Diets (TWD) alter behavior and cognition, cerebral hemodynamics (relative cerebral blood volume (rCBV)) and Abeta deposition in 8- and 15-month-old APP(swe)/PS1(dE9) mice. In addition we investigated whether changes in rCBV precede changes in Abeta deposition or vice versa. Mice were fed regular rodent chow, a TWD-, or a DHA-containing diet. Behavior, learning and memory were investigated, and rCBV was measured using contrast-enhanced MRI. The Abeta load was visualized immunohistochemically. We demonstrate that DHA altered rCBV in 8-month-old APP/PS1 and wild type mice[AU1]. In 15-month-old APP/PS1 mice DHA supplementation improved spatial memory, decreased Abeta deposition and slightly increased rCBV, indicating that a DHA-enriched diet can diminish AD-like pathology. In contrast, TWD diets decreased rCBV in 15-month-old mice. The present data indicate that long-term dietary interventions change AD-like pathology in APP/PS1 mice. Additionally, effects of the tested diets on vascular parameters were observed before effects on Abeta load were noted. These data underline the importance of vascular factors in the APP/PS1 mouse model of AD pathology.

Published
2009

22. Cognitive Decline in Type 2 Diabetes Mellitus and the Relation with Vascular Risk Factors: A Longitudinal Population-Based Study

Author

Post, H.W., Reijmer, Y.D. (Thesis Advisor), Berg, E. van den, Dijkerman, H.C., Post, H.W., Reijmer, Y.D. (Thesis Advisor), Berg, E. van den, and Dijkerman, H.C.

Abstract

Background/Aims Type 2 diabetes mellitus (T2DM) and co-morbid vascular risk factors (e.g. HbA1c, hypertension, obesity) are associated with decrements in cognitive functioning, especially in the elderly. We hypothesized that these cognitive decrements increase over time with advancing age. The current longitudinal study examined the development in cognitive functioning in T2DM over a 4-year interval. Methods An extensive neuropsychological assessment and vascular and metabolic risk factor profiles were obtained from 47 T2DM patients (mean age: 66.9 ± 5.6) and 26 matched-control participants (mean age: 63.4 ± 5.4). Cognitive test scores divided into five cognitive domains (Abstract Reasoning, Memory, Information Processing Speed, Attention and Executive Functioning and Visuoconstruction) and expressed as standardised z-scores, adjusted for age. Results T2DM patients performed worse than controls on the domains Abstract Reasoning (effect size (ES): -.07 to -.07), Memory (ES: -.21 to -.16), Information Processing Speed (ES: -.33 to -.54) and Attention and Executive Functioning (ES: -.16 to -.26), but this difference was only significant for the domain Information Processing Speed. No Time and GroupxTime interaction effects were observed in cognitive functioning. However, a trend for interaction was observed on the domain Information Processing Speed (p=.066). Body Mass Index was a predictor for cognitive decline on the domain Visuoconstruction (>BMI predicts better performance on Visuoconstruction) (p<.05). Conclusion Even though we did find changes in cognitive performance, contrary to our hypothesis accelerated cognitive decline was not observed in T2DM patients. Co-morbid vascular risk factors associated with T2DM, did not consistently predict worse cognitive performance. In this study sample BMI was related to performance on the domain Visuoconstruction.

Published
2009

25. Towards multicentre application of diffusion MRI in cerebral small vessel disease

Author

Brito Robalo, Bruno Miguel de, Biessels, G.J., Leemans, A.L.G., Reijmer, Y.D., Luca, A. de, and University Utrecht

Subjects
Diffusion MRI, Cerebral small vessel disease, brain connectivity, harmonization, thresholding
Abstract

The aim of the work described in this thesis was to advance the implementation of diffusion MRI in SVD research by exploring methods that improve its technical validity. The two key objectives were 1) to improve the validity of multicentre dMRI, by removing variability related to acquisition hardware in dMRI across sites with harmonization of the raw diffusion signal and 2) to improve the validity of dMRI-based network analyses, in the presence of pathology, by removing false positive connections with thresholding. We addressed our first key objective in Chapters 2 and 5, where we showed proof of concept of effective harmonization with data from five cohorts of patients with SVD and controls, using rotation invariant spherical harmonic (RISH) features. In chapter 2 we showed that the RISH method removes acquisition-related differences in scalar dMRI metrics between matched controls of different sites, while preserving disease-related effect sizes (i.e., differences between patients and controls and associations between dMRI metrics and markers of SVD). Consequently, the harmonized data could be pooled to increase sample size and infer associations between dMRI metrics and markers of SVD with improved power. In chapter 5 we applied RISH harmonization beyond the scalar metrics explored in Chapter 2, by investigating if it also improves cross-site consistency of brain networks. We demonstrated that harmonization helps to achieve more similar network architectures across sites. Furthermore, harmonization facilitated data pooling to infer patterns of network injury with improved sensitivity as compared to single centre datasets. We addressed our second key objective in chapters 3, 4 and 5 where we examined whether network thresholding increases consistency of brain networks in studies with cross-sectional design, longitudinal design and in multicentre analysis. In chapter 3 we proposed fixed-density thresholding as method to control for differences in network density (i.e., number of detected connections) when comparing networks of patients and controls. We showed that thresholding networks to a fixed density across all subjects preserves the original network architecture over a large range of thresholds and maintains the sensitivity to detected group-differences between patients with SVD and controls in global and local metrics. In this manner, networks can be compared across groups without the risk of measures being affected by density bias. In chapter 4, we tackled the effect of false positive connections causing low reproducibility of brain networks in longitudinal studies. We showed that weight-based thresholding improves scan-rescan network consistency in healthy young subjects (with relatively short-rescan inter¬vals) but also in patients with SVD scanned over long time periods. Importantly, we proved that thresholding preserves sensitivity to detect statistical group-differences between patients with low and high SVD burden. Finally, in chapter 5 we demonstrated that thresholding, in combination with RISH harmonization, helps to generate more consistent networks in multicentre data. In this analysis we showed that thresholding complements harmonization by reducing the number of false positives in the network, ultimately improving precision to detect patterns of network injury in multicentre data of patients SVD. Altogether, the work presented in this thesis shows the benefits of dMRI harmoni¬zation by making data more comparable across centres and enabling data pooling to increase sample size. Our work also shows that advantages of network thresholding by improving precision of network analysis, paving the way for robust large scale dMRI network analysis in SVD.

Published
2022

26. DHA and cholesterol containing diets influence Alzheimer-like pathology, cognition and cerebral vasculature in APPswe/PS1dE9 mice

Author

Hooijmans, C.R., Van der Zee, C.E.E.M., Dederen, P.J., Brouwer, K.M., Reijmer, Y.D., van Groen, T., Broersen, L.M., Lütjohann, D., Heerschap, A., and Kiliaan, A.J.

Subjects
*DOCOSAHEXAENOIC acid, *CHOLESTEROL, *ISOPENTENOIDS, *HEMODYNAMICS
Abstract

Abstract: Cholesterol and docosahexenoic acid (DHA) may affect degenerative processes in Alzheimer''s Disease (AD) by influencing Aβ metabolism indirectly via the vasculature. We investigated whether DHA-enriched diets or cholesterol-containing Typical Western Diets (TWD) alter behavior and cognition, cerebral hemodynamics (relative cerebral blood volume (rCBV)) and Aβ deposition in 8- and 15-month-old APPswe/PS1dE9 mice. In addition we investigated whether changes in rCBV precede changes in Aβ deposition or vice versa. Mice were fed regular rodent chow, a TWD-, or a DHA-containing diet. Behavior, learning and memory were investigated, and rCBV was measured using contrast-enhanced MRI. The Aβ load was visualized immunohistochemically. We demonstrate that DHA altered rCBV in 8-month-old APP/PS1 and wild type mice[AU1]. In 15-month-old APP/PS1 mice DHA supplementation improved spatial memory, decreased Aβ deposition and slightly increased rCBV, indicating that a DHA-enriched diet can diminish AD-like pathology. In contrast, TWD diets decreased rCBV in 15-month-old mice. The present data indicate that long-term dietary interventions change AD-like pathology in APP/PS1 mice. Additionally, effects of the tested diets on vascular parameters were observed before effects on Aβ load were noted. These data underline the importance of vascular factors in the APP/PS1 mouse model of AD pathology. [Copyright &y& Elsevier]

Published
2009
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