We performed a systematic review and meta-analysis on prospective studies that provided risk estimates for the impact of 3 different MRI markers of small vessel disease (SVD), namely white matter... Show moreWe performed a systematic review and meta-analysis on prospective studies that provided risk estimates for the impact of 3 different MRI markers of small vessel disease (SVD), namely white matter hyperintensities (WMH), cerebral microbleeds (CMB) and lacunes, on cognitive decline in relatively healthy older adults without cognitive deficits at baseline. A total of 23 prospective studies comprising 11,486 participants were included for analysis. Extracted data was pooled, reviewed and meta-analysed separately for global cognition, executive function, memory and attention. The pooled effect size for the association between cerebral SVD and cognitive decline was for global cognition -0.10 [-0.14; -0.05], for executive functioning -0.18 [-0.24; - 0.11], for memory -0.12 [-0.17; -0.07], and for attention -0.17 [-0.23; -0.11]. Results for the association of individual MRI markers of cerebral SVD were statistically significant for WMH and global cognition -0.15 [-0.24; -0.06], WMH and executive function -0.23 [-0.33; -0.13], WMH and memory -0.19 [-0.29; -0.09], WMH and attention -0.24 [-0.39; -0.08], CMB and executive function -0.07 [-0.13; -0.02], CMB and memory -0.11 [-0.21; -0.02] and CMB and attention -0.13 [-0.25; -0.02]. In conclusion, presence of MRI markers of cerebral SVD were found to predict an increased risk of cognitive decline in relatively healthy older adults. While WMH were found to significantly affect all cognitive domains, CMB influenced decline in executive functioning over time as well as (in some studies) decline in memory and attention. Show less
Keller, J.A.; Sigurdsson, S.; Klaassen, K.; Hirschler, L.; Buchem, M.A. van; Launer, L.J.; ... ; Bresser, J.H.J.M. de 2023
INTRODUCTIONWe aimed to investigate the association between white matter hyperintensity (WMH) shape and volume and the long-term dementia risk in community-dwelling older adults. METHODSThree... Show moreINTRODUCTIONWe aimed to investigate the association between white matter hyperintensity (WMH) shape and volume and the long-term dementia risk in community-dwelling older adults. METHODSThree thousand seventy-seven participants (mean age: 75.6 +/- 5.2 years) of the Age Gene/Environment Susceptibility (AGES)-Reykjavik study underwent baseline 1.5T brain magnetic resonance imaging and were followed up for dementia (mean follow-up: 9.9 +/- 2.6 years). RESULTSMore irregular shape of periventricular/confluent WMH (lower solidity (hazard ratio (95% confidence interval) 1.34 (1.17 to 1.52), p < .001) and convexity 1.38 (1.28 to 1.49), p < .001); higher concavity index 1.43 (1.32 to 1.54), p < .001) and fractal dimension 1.45 (1.32 to 1.58), p < .001)), higher total WMH volume (1.68 (1.54 to 1.87), p < .001), higher periventricular/confluent WMH volume (1.71 (1.55 to 1.89), p < .001), and higher deep WMH volume (1.17 (1.08 to 1.27), p < .001) were associated with an increased long-term dementia risk. DISCUSSIONWMH shape markers may in the future be useful in determining patient prognosis and may aid in patient selection for future preventive treatments in community-dwelling older adults. Show less
Drenth, N.; Foster-Dingley, J.C.; Bertens, A.S.; Ottenheim, N.R.; Mast, R.C. van der; Rombouts, S.A.R.B.; ... ; Grond, J. van der 2023
Ageing is associated with functional reorganization that is mainly characterized by declining functional connectivity due to general neurodegeneration and increasing incidence of disease.... Show moreAgeing is associated with functional reorganization that is mainly characterized by declining functional connectivity due to general neurodegeneration and increasing incidence of disease. Functional connectivity has been studied across the lifespan; however, there is a paucity of research within the older groups (>= 75 years) where neurodegeneration and disease prevalence are at its highest. In this cross-sectional study, we investigated associations between age and functional connectivity and the influence of cerebral small vessel disease (CSVD)-a common age-related morbidity-in 167 community-dwelling older adults aged 75-91 years (mean = 80.3 +/- 3.8). Resting-state functional MRI was used to determine functional connectivity within ten standard networks and calculate the whole brain graph theoretical measures global efficiency and clustering coefficient. CSVD features included white matter hyperintensities, lacunar infarcts, cerebral microbleeds, and atrophy that were assessed in each individual and a composite score was calculated. Both main and interaction effects (age*CSVD features) on functional connectivity were studied. We found stable levels of functional connectivity across the age range. CSVD was not associated with functional connectivity measures. To conclude, our data show that the functional architecture of the brain is relatively unchanged after 75 years of age and not differentially affected by individual levels of vascular pathology. Show less
Al-Nofal, M.; Boer, I. de; Agirman, S.; Wilms, A.E.; Najafabadi, A.Z.H.; Terwindt, G.M.; Notting, I.C. 2022
Background: The brain and retina share many neuronal and vasculature characteristics. We investigated the retinal microvasculature in patients with a monogenic vasculopathy using optical coherence... Show moreBackground: The brain and retina share many neuronal and vasculature characteristics. We investigated the retinal microvasculature in patients with a monogenic vasculopathy using optical coherence tomography angiography (OCTA). OCT-A is a novel precise non-invasive imaging method that may provide biomarkers suitable for diagnosis and follow-up of small vessel diseases. Methods: In this exploratory cross-sectional study, eleven RVCL-S patients and eleven age-matched healthy control participants were included. The size of the foveal avascular zone (FAZ) and the vascular density of the superficial capillary networks in the retina were measured by OCT-A. Results: The symptomatic and presymptomatic patients showed significantly lower vascular density values than controls in the foveal region [median (IQR) 18.2% (15.8-18.6) vs. 24.4% (21.5-26.8) (p < 0.001), 29.8% (29.6-30.8) vs. 33.2% (32.0-33.6) (p = 0.002), respectively]. The FAZ was significantly larger in the symptomatic RVCL-S patients than in the control group [13,416 square pixels [7,529-22,860] vs. 1,405 square pixels [1,344-2,470] (p < 0.001)]. No significant difference was identified in measurements of FAZ comparing presymptomatic and controls. Conclusion: Our findings with OCT-A demonstrated that RVCL-S causes an increase in the size of the FAZ in symptomatic RVCL-S patients compared to healthy participants. Moreover, there is a decrease in vessel density in the superficial capillary networks in both symptomatic and presymptomatic patients. In the future, newly developed precise objective instruments such as OCT (-A) may provide important tools in determining disease activity for follow up of common small vessel diseases. Show less
Bijkerk, R.; Kallenberg, M.H.; Zijlstra, L.E.; Berg, B.M. van den; Bresser, J. de; Hammer, S.; ... ; Mooijaart, S. 2022
Background: The prevalence of end-stage renal disease (ESRD) is increasing worldwide, with the majority of new ESRD cases diagnosed in patients >60 years of age. These older patients are at... Show moreBackground: The prevalence of end-stage renal disease (ESRD) is increasing worldwide, with the majority of new ESRD cases diagnosed in patients >60 years of age. These older patients are at increased risk for impaired cognitive functioning, potentially through cerebral small vessel disease (SVD). Novel markers of vascular integrity may be of clinical value for identifying patients at high risk for cognitive impairment. Methods: We aimed to associate the levels of angiopoietin-2 (Ang-2), asymmetric dimethylarginine and a selection of eight circulating angiogenic microRNAs (miRNAs) with SVD and cognitive impairment in older patients reaching ESRD that did not yet initiate renal replacement therapy (n = 129; mean age 75.3 years, mean eGFR 16.4 mL/min). We assessed brain magnetic resonance imaging changes of SVD (white matter hyperintensity volume, microbleeds and the presence of lacunes) and measures of cognition in domains of memory, psychomotor speed and executive function in a neuropsychological test battery. Results: Older patients reaching ESRD showed an unfavourable angiogenic profile, as indicated by aberrant levels of Ang-2 and five angiogenic miRNAs (miR-27a, miR-126, miR-132, miR-223 and miR-326), compared with healthy persons and patients with diabetic nephropathy. Moreover, Ang-2 was associated with SVD and with the domains of psychomotor speed and executive function, while miR-223 and miR-29a were associated with memory function. Conclusions: Taken together, these novel angiogenic markers might serve to identify older patients with ESRD at risk of cognitive decline, as well as provide insights into the underlying (vascular) pathophysiology. Show less
Knaak, C.; Kant, I.M.J.; Lammers-Lietz, F.; Spies, C.; Witkamp, T.D.; Winterer, G.; ... ; Bresser, J. de 2021
BACKGROUND AND PURPOSE: Hyperglycemia can lead to an increased rate of apoptosis of microglial cells and to damaged neurons. The relation between hyperglycemia and cerebrovascular markers on MRI is... Show moreBACKGROUND AND PURPOSE: Hyperglycemia can lead to an increased rate of apoptosis of microglial cells and to damaged neurons. The relation between hyperglycemia and cerebrovascular markers on MRI is unknown. Our aim was to study the association between intraoperative hyperglycemia and cerebrovascular markers.METHODS: In this further analysis of a subgroup investigation of the BIOCOG study, 65 older non-demented patients (median 72 years) were studied who underwent elective surgery of >= 60 minutes. Intraoperative blood glucose maximum was determined retrospectively in each patient. In these patients, preoperatively and at 3 months follow-up a MRI scan was performed and white matter hyperintensity (WMH) volume and shape, infarcts, and perfusion parameters were determined. Multivariable logistic regression analyses were performed to determine associations between preoperative cerebrovascular markers and occurrence of intraoperative hyperglycemia. Linear regression analyses were performed to assess the relation between intraoperative hyperglycemia and pre- to postoperative changes in WMH volume. Associations between intraoperative hyperglycemia and postoperative WMH volume at 3 months follow-up were also assessed by linear regression analyses.RESULTS: Eighteen patients showed intraoperative hyperglycemia (glucose maximum >= 150 mg/dL). A preoperative more smooth shape of periventricular and confluent WMH was related to the occurrence of intraoperative hyperglycemia [convexity: OR 33.318 (95 % CI (1.002 - 1107.950); p = 0.050]. Other preoperative cerebrovascular markers were not related to the occurrence of intraoperative hyperglycemia. Intraoperative hyperglycemia showed no relation with pre- to postoperative changes in WMH volume nor with postoperative WMH volume at 3 months follow-up.CONCLUSIONS: We found that a preoperative more smooth shape of periventricular and confluent WMH was related to the occurrence of intraoperative hyperglycemia. These findings may suggest that a similar underlying mechanism leads to a certain pattern of vascular brain abnormalities and an increased risk of hyperglycemia. Show less
Heinen, R.; Groeneveld, O.N.; Barkhof, F.; Bresser, J. de; Exalto, L.G.; Kuijf, H.J.; ... ; TRACE-VCI Study Grp 2020
IntroductionIt is unknown whether different types of small vessel disease (SVD), differentially relate to brain atrophy and if co-occurring Alzheimer's disease pathology affects this relation... Show moreIntroductionIt is unknown whether different types of small vessel disease (SVD), differentially relate to brain atrophy and if co-occurring Alzheimer's disease pathology affects this relation.MethodsIn 725 memory clinic patients with SVD (mean age 67 +/- 8 years, 48% female) we compared brain volumes of those with moderate/severe white matter hyperintensities (WMHs; n = 326), lacunes (n = 132) and cerebral microbleeds (n = 321) to a reference group with mild WMHs (n = 197), also considering cerebrospinal fluid (CSF) amyloid status in a subset of patients (n = 488).ResultsWMHs and lacunes, but not cerebral microbleeds, were associated with smaller gray matter (GM) volumes. In analyses stratified by CSF amyloid status, WMHs and lacunes were associated with smaller total brain and GM volumes only in amyloid-negative patients. SVD-related atrophy was most evident in frontal (cortical) GM, again predominantly in amyloid-negative patients.DiscussionAmyloid status modifies the differential relation between SVD lesion type and brain atrophy in memory clinic patients. Show less
Rooden, S. van; Berg-Huysmans, A.A. van den; Croll, P.H.; Labadie, G.; Hayes, J.M.; Viviano, R.; ... ; Damoiseaux, J.S. 2018
Background:Research in older adults with subjective cognitive decline (SCD) has mainly focused on Alzheimer’s disease (AD)-related MRI markers, such as hippocampal volume. However, small vessel... Show moreBackground:Research in older adults with subjective cognitive decline (SCD) has mainly focused on Alzheimer’s disease (AD)-related MRI markers, such as hippocampal volume. However, small vessel disease (SVD) is currently established as serious comorbidity in dementia and its preliminary stages. It is therefore important to examine SVD markers in addition to AD markers in older adults presenting with SCD.Objective:The aim of our study was to elucidate the role of SVD markers in late middle-aged to older adults with and without SCD in addition to the commonly found role of AD markers (hippocampal volume).Methods:67 healthy late middle-aged to older adults participated in this study (mean age 68 years); 25 participants with SCD and 42 participants without SCD. We evaluated quantitative as well as qualitative AD markers (i.e., hippocampal volume and medial temporal lobe atrophy (MTA) scale) and SVD markers (i.e., white matter hyperintensities (WMH) volume, Fazekas scale, microbleeds, and lacunar infarcts), and neuropsychological function and amount of memory complaints.Results:We found a significant effect of SCD on hippocampal atrophy, as assessed using the MTA scale, but not on hippocampal volume. In addition, we found a significant effect of SCD, and amount of memory complaints, on WMH volume and Fazekas score, suggesting larger WMH volumes in participants with SCD.Conclusion:SVD MRI markers are related to amount of memory complaints, in addition to the commonly observed AD MRI markers, as demonstrated by the greater WMHs in healthy late middle-aged to older adults with SCD. Show less
Rooden, S. van; Berg-Huysmans, A.A. van den; Croll, P.H.; Labadie, G.; Hayes, J.M.; Viviano, R.; ... ; Damoiseaux, J.S. 2018
