Esther M.C. van Leijsen

Nonlinear temporal dynamics of cerebral small vessel disease: The RUN DMC study.

Objective: To investigate the temporal dynamics of cerebral small vessel disease (SVD) by 3 consecutive assessments over a period of 9 years, distinguishing progression from regression. Methods: Changes in SVD markers of 276 participants of the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Imaging Cohort (RUN DMC) cohort were assessed at 3 time points over 9 years. We assessed white matter hyperintensities (WMH) volume by semiautomatic segmentation and rated lacunes and microbleeds manually. We categorized baseline WMH severity as mild, moderate, or severe according to the modified Fazekas scale. We performed mixed-effects regression analysis including a quadratic term for increasing age. Results: Mean WMH progression over 9 years was 4.7 mL (0.54 mL/y; interquartile range 0.95–5.5 mL), 20.3% of patients had incident lacunes (2.3%/y), and 18.9% had incident microbleeds (2.2%/y). WMH volume declined in 9.4% of the participants during the first follow-up interval, but only for 1 participant (0.4%) throughout the whole follow-up. Lacunes disappeared in 3.6% and microbleeds in 5.7% of the participants. WMH progression accelerated over time: including a quadratic term for increasing age during follow-up significantly improved the model (p < 0.001). SVD progression was predominantly seen in participants with moderate to severe WMH at baseline compared to those with mild WMH (odds ratio [OR] 35.5, 95% confidence interval [CI] 15.8–80.0, p < 0.001 for WMH progression; OR 5.7, 95% CI 2.8–11.2, p < 0.001 for incident lacunes; and OR 2.9, 95% CI 1.4–5.9, p = 0.003 for incident microbleeds). Conclusions: SVD progression is nonlinear, accelerating over time, and a highly dynamic process, with progression interrupted by reduction in some, in a population that on average shows progression.

Late-onset depressive symptoms increase the risk of dementia in small vessel disease

Objective: We prospectively investigated the role of depressive symptoms (DS) on all-cause dementia in a population with small vessel disease (SVD), considering onset age of DS and cognitive performance. Methods: The RUN DMC study (Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort) is a prospective cohort study among 503 older adults with SVD on MRI without dementia at baseline (2006), with a follow-up of 5 years (2012). Kaplan-Meier curves stratified for DS and dementia risk were compared using log-rank test. We calculated hazard ratios using Cox regression analyses. Results: Follow-up was available for 496 participants (mean baseline age 65.6 years [SD 8.8]; mean follow-up time 5.2 years). All-cause dementia developed in 41 participants. The 5.5-year dementia risk was higher in those with DS (hazard ratio 2.7, 95% confidence interval 1.4–5.2), independent of confounders. This was driven by those with late-onset DS. Five-year cumulative risk difference for dementia was higher in participants with depressive symptoms who had high baseline cognitive performance (no DS 0.0% vs DS 6.9%, log-rank p < 0.001) compared with those who had low cognitive performance at baseline. Conclusions: Late-onset DS increases dementia risk, independent of SVD. Especially in those with relatively high cognitive performance, DS indicate a higher risk. In contrast to current practice, clinicians should monitor those with DS who also show relatively good cognitive test scores.

Progression of White Matter Hyperintensities Preceded by Heterogeneous Decline of Microstructural Integrity

Background and Purpose— White matter hyperintensities (WMH) are frequently seen on neuroimaging of elderly and are associated with cognitive decline and the development of dementia. Yet, the temporal dynamics of conversion of normal-appearing white matter (NAWM) into WMH remains unknown. We examined whether and when progression of WMH was preceded by changes in fluid-attenuated inversion recovery and diffusion tensor imaging values, thereby taking into account differences between participants with mild versus severe baseline WMH. Methods— From 266 participants of the RUN DMC study (Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Imaging Cohort), we semiautomatically segmented WMH at 3 time points for 9 years. Images were registered to standard space through a subject template. We analyzed differences in baseline fluid-attenuated inversion recovery, fractional anisotropy, and mean diffusivity (MD) values and changes in MD values over time between 4 regions: (1) remaining NAWM, (2) NAWM converting into WMH in the second follow-up period, (3) NAWM converting into WMH in the first follow-up period, and (4) WMH. Results— NAWM converting into WMH in the first or second time interval showed higher fluid-attenuated inversion recovery and MD values than remaining NAWM. MD values in NAWM converting into WMH in the first time interval were similar to MD values in WMH. When stratified by baseline WMH severity, participants with severe WMH had higher fluid-attenuated inversion recovery and MD and lower fractional anisotropy values than participants with mild WMH, in all areas including the NAWM. MD values in WMH and in NAWM that converted into WMH continuously increased over time. Conclusions— Impaired microstructural integrity preceded conversion into WMH and continuously declined over time, suggesting a continuous disease process of white matter integrity loss that can be detected using diffusion tensor imaging even years before WMH become visible on conventional neuroimaging. Differences in microstructural integrity between participants with mild versus severe WMH suggest heterogeneity of both NAWM and WMH, which might explain the clinical variability observed in patients with similar small vessel disease severity.

Plasma Aβ (Amyloid-β) Levels and Severity and Progression of Small Vessel Disease

Background and Purpose— Cerebral small vessel disease (SVD) is a frequent pathology in aging and contributor to the development of dementia. Plasma A&bgr; (amyloid &bgr;) levels may be useful as early biomarker, but the role of plasma A&bgr; in SVD remains to be elucidated. We investigated the association of plasma A&bgr; levels with severity and progression of SVD markers. Methods— We studied 487 participants from the RUN DMC study (Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Imaging Cohort) of whom 258 participants underwent 3 MRI assessments during 9 years. We determined baseline plasma A&bgr;38, A&bgr;40, and A&bgr;42 levels using ELISAs. We longitudinally assessed volume of white matter hyperintensities semiautomatically and manually rated lacunes and microbleeds. We analyzed associations between plasma A&bgr; and SVD markers by ANCOVA adjusted for age, sex, and hypertension. Results— Cross-sectionally, plasma A&bgr;40 levels were elevated in participants with microbleeds (mean, 205.4 versus 186.4 pg/mL; P<0.01) and lacunes (mean, 194.8 versus 181.2 pg/mL; P<0.05). Both A&bgr;38 and A&bgr;40 were elevated in participants with severe white matter hyperintensities (A&bgr;38, 25.3 versus 22.7 pg/mL; P<0.01; A&bgr;40, 201.8 versus 183.3 pg/mL; P<0.05). Longitudinally, plasma A&bgr;40 levels were elevated in participants with white matter hyperintensity progression (mean, 194.6 versus 182.9 pg/mL; P<0.05). Both A&bgr;38 and A&bgr;40 were elevated in participants with incident lacunes (A&bgr;38, 24.5 versus 22.5 pg/mL; P<0.05; A&bgr;40, 194.9 versus 181.2 pg/mL; P<0.01) and A&bgr;42 in participants with incident microbleeds (62.8 versus 60.4 pg/mL; P<0.05). Conclusions— Plasma A&bgr; levels are associated with both presence and progression of SVD markers, suggesting that A&bgr; pathology might contribute to the development and progression of SVD. Plasma A&bgr; levels might thereby serve as inexpensive and noninvasive measure for identifying individuals with increased risk for progression of SVD.

Cerebral small vessel disease: from a focal to a global perspective

Cerebral small vessel disease (SVD) is commonly observed on neuroimaging among elderly individuals and is recognized as a major vascular contributor to dementia, cognitive decline, gait impairment, mood disturbance and stroke. However, clinical symptoms are often highly inconsistent in nature and severity among patients with similar degrees of SVD on brain imaging. Here, we provide a new framework based on new advances in structural and functional neuroimaging that aims to explain the remarkable clinical variation in SVD. First, we discuss the heterogeneous pathology present in SVD lesions despite an identical appearance on imaging and the perilesional and remote effects of these lesions. We review effects of SVD on structural and functional connectivity in the brain, and we discuss how network disruption by SVD can lead to clinical deficits. We address reserve and compensatory mechanisms in SVD and discuss the part played by other age-related pathologies. Finally, we conclude that SVD should be considered a global rather than a focal disease, as the classically recognized focal lesions affect remote brain structures and structural and functional network connections. The large variability in clinical symptoms among patients with SVD can probably be understood by taking into account the heterogeneity of SVD lesions, the effects of SVD beyond the focal lesions, the contribution of neurodegenerative pathologies other than SVD, and the interaction with reserve mechanisms and compensatory mechanisms.Cerebral small vessel disease (SVD) is associated with highly heterogeneous clinical symptoms. This Review considers how new advances in structural and functional neuroimaging have revealed ways in which focal lesions can affect remote brain regions and lead to global dysfunction, resulting in the variable presentation of SVD.Key pointsCerebral small vessel disease (SVD) is associated with a remarkable degree of variation in clinical symptoms — both in nature and in severity — that cannot be explained fully by conventional markers of SVD.Conventional MRI does not capture the heterogeneity present in SVD lesions with a similar appearance and reveals only the tip of the iceberg of the total SVD-related brain damage.SVD affects brain tissue beyond the commonly recognized focal lesions by inducing a cascade of events that spread from the initial lesion to remote brain areas, which probably contributes to clinical outcome.SVD disturbs structural and functional network connectivity and thereby disrupts efficient communication in brain networks, which is necessary for functional performance.Brain resilience protects against clinical deterioration caused by SVD via reserve and compensatory mechanisms, which explains the clinical variation observed in patients with apparently equal SVD lesion burden.The clinical notion that SVD mostly constitutes a subcortical disease of focal lesions requires reconsideration.

Serum Neurofilament Light Chain Levels Are Related to Small Vessel Disease Burden

Background and Purpose Neurofilament light chain (NfL) is a blood marker for neuroaxonal damage. We assessed the association between serum NfL and cerebral small vessel disease (SVD), which is highly prevalent in elderly individuals and a major cause of stroke and vascular cognitive impairment. Methods Using a cross-sectional design, we studied 53 and 439 patients with genetically defined SVD (Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy [CADASIL]) and sporadic SVD, respectively, as well as 93 healthy controls. Serum NfL was measured by an ultrasensitive single-molecule array assay. We quantified magnetic resonance imaging (MRI) markers of SVD, i.e., white matter hyperintensity volume, lacune volume, brain volume, microbleed count, and mean diffusivity obtained from diffusion tensor imaging. Clinical characterization included neuropsychological testing in both SVD samples. CADASIL patients were further characterized for focal neurological deficits (National Institutes of Health stroke scale [NIHSS]) and disability (modified Rankin scale [mRS]). Results Serum NfL levels were elevated in both SVD samples (P<1e-05 compared with controls) and associated with all SVD MRI markers. The strongest association was found for mean diffusivity (CADASIL, R2=0.52, P=1.2e-09; sporadic SVD, R2=0.21, P<1e-15). Serum NfL levels were independently related to processing speed performance (CADASIL, R2=0.27, P=7.6e-05; sporadic SVD, R2=0.06, P=4.8e-08), focal neurological symptoms (CADASIL, NIHSS, P=4.2e-05) and disability (CADASIL, mRS, P=3.0e-06). Conclusions We found serum NfL levels to be associated with both imaging and clinical features of SVD. Serum NfL might complement MRI markers in assessing SVD burden. Importantly, SVD needs to be considered when interpreting serum NfL levels in the context of other age-related diseases.

Memory decline in elderly with cerebral small vessel disease explained by temporal interactions between white matter hyperintensities and hippocampal atrophy

White matter hyperintensities (WMH) constitute the visible spectrum of cerebral small vessel disease (SVD) markers and are associated with cognitive decline, although they do not fully account for memory decline observed in individuals with SVD. We hypothesize that WMH might exert their effect on memory decline indirectly by affecting remote brain structures such as the hippocampus. We investigated the temporal interactions between WMH, hippocampal atrophy and memory decline in older adults with SVD. Five hundred and three participants of the RUNDMC study underwent neuroimaging and cognitive assessments up to 3 times over 8.7 years. We assessed WMH volumes semi‐automatically and calculated hippocampal volumes (HV) using FreeSurfer. We used linear mixed effects models and causal mediation analyses to assess both interaction and mediation effects of hippocampal atrophy in the associations between WMH and memory decline, separately for working memory (WM) and episodic memory (EM). Linear mixed effect models revealed that the interaction between WMH and hippocampal volumes explained memory decline (WM: β = .067; 95%CI[.024–0.111]; p < .01; EM: β = .061; 95%CI[.025–.098]; p < .01), with better model fit when the WMH*HV interaction term was added to the model, for both WM (likelihood ratio test, χ2[1] = 9.3, p < .01) and for EM (likelihood ratio test, χ2[1] = 10.7, p < .01). Mediation models showed that both baseline WMH volume (β = −.170; p = .001) and hippocampal atrophy (β = 0.126; p = .009) were independently related to EM decline, but the effect of baseline WMH on EM decline was not mediated by hippocampal atrophy (p value indirect effect: 0.572). Memory decline in elderly with SVD was best explained by the interaction of WMH and hippocampal volumes. The relationship between WMH and memory was not causally mediated by hippocampal atrophy, suggesting that memory decline during aging is a heterogeneous condition in which different pathologies contribute to the memory decline observed in elderly with SVD.

Baseline Cerebral Small Vessel Disease Is Not Associated with Gait Decline After Five Years

Cerebral small vessel disease (SVD) is cross‐sectionally associated with gait disturbances, however, the relation between baseline SVD and gait decline over time is uncertain. Furthermore, diffusion tensor imaging (DTI) studies on gait decline are currently lacking.

ASSOCIATIONS OF PLASMA AMYLOID BETA LEVELS WITH SEVERITY AND PROGRESSION OF CEREBRAL SMALL VESSEL DISEASE

Background: N-terminally truncated and pyroglutamate modified Ab peptide starting at position 3 and ending with amino acid 42 (Ab3(pE)-42) has been previously shown to represent a major species in the brain of Alzheimer’s Disease (AD) patients. In addition, N-truncated Ab4-42 is another highly abundant Ab peptide in AD brain. Our recent observations revealed that Ab4-42 is as toxic as Ab3(pE)-42 and also shows high aggregation propensity. The aim of the present project is to study the direct effect of the combination of Ab3(pE)-42 and Ab4-42 on ongoing AD pathology in transgenic mice.Methods:Bigenic mice were generated by crossing the established TBA42 and Tg4-42 mouse models expressing the N-truncated Ab peptides Ab3(pE)-42 and Ab4-42 respectively. After generation of the bigenic mice, detailed phenotypical characterization was performed. In order to evaluate motor deficits, the inverted grid, the balance beam and the string suspension tasks were performed. The elevated plus maze was used to study anxiety levels. Immunostaininings were performed to evaluate the amyloid pathology. Results: In the elevated plus maze and all motor tests, bigenic mice showed an aggravated phenotype compared to mice expressing only Ab3(pE)-42 or Ab4-42. Also, bigenic mice showed higher accumulation of Ab in the motor neurons of the spinal cord and plaque load. Conclusions:We show that Ab3(pE)-42 and Ab4-42, when combined, aggravate the behavioral phenotype in an age dependent manner and provide in vivo evidence that both peptides together are likely playing an important role in AD pathology.