Long-Term Longitudinal Course of Cognitive and Motor Symptoms in Patients With Cerebral Small Vessel Disease.

BACKGROUND AND OBJECTIVES: Patients with cerebral small vessel disease (SVD) show a heterogenous clinical course. The aim of the current study was to investigate the longitudinal course of cognitive and motor function in patients who developed parkinsonism, dementia, both, or none. METHODS: Participants were from the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort study, a prospective cohort of patients with SVD. Parkinsonism and dementia were, respectively, diagnosed according to the UK Parkinson's Disease Society brain bank criteria and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria for major neurocognitive disorder. Linear and generalized linear mixed-effect analyses were used to study the longitudinal course of motor and cognitive tasks. RESULTS: After a median follow-up of 12.8 years (interquartile range 10.2-15.3), 132 of 501 (26.3%) participants developed parkinsonism, dementia, or both. Years before diagnosis of these disorders, participants showed distinct clinical trajectories from those who developed none: Participant who developed parkinsonism had an annual percentage of 22% (95% CI 18%-27%) increase in motor part of the Unified Parkinson's Disease Rating Scale score. This was significantly higher than the 16% (95% CI 14%-18%) of controls, mainly because of a steep increase in bradykinesia and posture and gait disturbances. When they developed dementia as well, the increase in Timed Up and Go Test time of 0.73 seconds per year (95% CI 0.58-0.87) was significantly higher than the 0.20 seconds per year increase (95% CI 0.16-0.23) of controls. All groups, including the participants who developed parkinsonism without dementia, showed a faster decline in executive function compared with controls: Annual decline in Z-score was -0.07 (95% CI -0.10 to -0.05), -0.09 (95% CI -0.11 to -0.08), and -0.11 (95% CI -0.14 to -0.08) for participants who developed, respectively, parkinsonism, dementia, and both parkinsonism and dementia. These declines were all significantly faster than the annual decline in Z-score of 0.07 (95% CI -0.10 to -0.05) of controls. DISCUSSION: A distinct pattern in deterioration of clinical markers is visible in patients with SVD, years before the diagnosis of parkinsonism and dementia. This knowledge aids early identification of patients with a high risk of developing these disorders.

Network structure-function coupling and neurocognition in cerebral small vessel disease.

BACKGROUND: Cerebral small vessel disease is a leading cause of cognitive decline and vascular dementia. Small vessel disease pathology changes structural brain networks, but its impact on functional networks remains poorly understood. Structural and functional networks are closely coupled in healthy individuals, and decoupling is associated with clinical symptoms in other neurological conditions. We tested the hypothesis that structural-functional network coupling is related to neurocognitive outcomes in 262 small vessel disease patients. METHODS: Participants underwent multimodal magnetic resonance imaging and cognitive assessment in 2011 and 2015. Structural connectivity networks were reconstructed using probabilistic diffusion tractography, while functional connectivity networks were estimated from resting-state functional magnetic resonance imaging. Structural and functional networks were then correlated to calculate a measure of structural-functional network coupling for each participant. RESULTS: Lower whole-brain coupling was associated with reduced processing speed and greater apathy both cross-sectionally and longitudinally. In addition, coupling within the cognitive control network was associated with all cognitive outcomes, suggesting that neurocognitive outcomes in small vessel disease may be related to the functioning of this intrinsic connectivity network. CONCLUSIONS: Our work demonstrates the influence of structural-functional connectivity network decoupling in small vessel disease symptomatology. Cognitive control network function may be investigated in future studies.

Risk of Dementia and Structural Brain Changes Following Nonneurological Infections During 9-Year Follow-Up.

OBJECTIVES: Given the strong association between systemic inflammation and cognitive decline, we aimed to determine whether nonneurologic infections are associated with accelerated cognitive decline and structural changes in the brain using pre- and post-infection neuropsychologic assessments and repeated brain MR images. DESIGN: Additional analysis of the prospective observational Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort study. SETTING: Single-center study at the Radboud university medical center, Nijmegen, The Netherlands, between January 2006 and September 2015. PATIENTS: Five-hundred three participants (50-85 yr old) with cerebral small vessel disease were included and followed for 9 years. MEASUREMENTS AND MAIN RESULTS: Participants underwent repeated cognitive measurements and brain MRI. Infectious events were collected. Sepsis episodes were analyzed, and additionally, patients were stratified in three groups: having had a severe infectious episode (e.g., sepsis or hospitalization for infection), a mild, or no infectious episode. Development of dementia, trajectories of cognition, and structural brain changes on MRI in the subsequent follow-up periods were compared between the groups. Complete infectious data were available from 331 patients (mean age 64 ± 8 yr, 57% males). Twenty-nine participants (9%) suffered from a sepsis episode, 69 (21%) from a severe, 201 (61%) from a mild, and 61 (18%) had no infectious episode during follow-up. After correction for age, baseline cognition, and brain volume, each sepsis episode remained associated with an 82% increased risk to develop dementia within the follow-up period (hazard ratio, 1.82; 95% CI, 1.07-3.10; p = 0.027). Infections had no effect on the trajectory of structural changes to the brain after correction for baseline differences. CONCLUSIONS: In this 9-year observational follow-up study, sepsis episodes were associated with subsequent development of dementia. Nonneurologic infections had no effect on the trajectory of structural cerebral changes.

Structural network efficiency predicts cognitive decline in cerebral small vessel disease.

Cerebral small vessel disease (SVD) is a common disease in older adults and a major contributor to vascular cognitive impairment and dementia. White matter network damage is a potentially important mechanism by which SVD causes cognitive impairment. Earlier studies showed that a higher degree of white matter network damage, indicated by lower global efficiency (a graph-theory measure assessing efficiency of network information transfer), was associated with lower scores on cognitive performance independent of MRI markers for SVD. However, it is unknown whether this global efficiency index is the strongest predictor for cognitive impairment, as there is a wide range of network measures. Here, we investigate which network measure is the most informative in explaining baseline cognitive performance and decline over a period of 8.7 years in SVD. We used data from the Radboud University Nijmegen Diffusion tensor and MRI Cohort (RUN DMC), which included 436 participants without dementia (65.2 ± 8.8 years) but with evidence of SVD on neuroimaging. Binarized and weighted structural brain networks were reconstructed using diffusion tensor imaging and deterministic streamlining. Using graph-theory, we calculated 21 global network measures and performed linear regression analyses, elastic net analysis and linear mixed effect models to compare these measures. All analyses were adjusted for potential confounders (age, sex, educational level, depressive symptoms and conventional SVD MRI-markers (e.g. white matter hyperintensities (WMH), lacunes of presumed vascular origin and microbleeds). The elastic net analyses showed that, at baseline, global efficiency had the strongest association with cognitive index (CI), while characteristic path length showed the strongest association with psychomotor speed (PMS) and memory. Binary local efficiency showed the strongest association with attention & executive function (A&EF). In addition, linear mixed-effect models demonstrated that baseline global efficiency predicts decline in CI (χ2(1) = 8.18, p = 0.004),PMS (χ2(1) = 7.75, p = 0.005), memory (χ2(1) = 27.28, p = 0.000) over time and that binary local efficiency predicts decline in A&EF (χ2(1) = 8.66, p = 0.003) over time. Our results suggest that among all network measures, network efficiency measures, i.e. global efficiency and local efficiency, are the strongest predictors for cognitive functions at cross-sectional level and also predict faster cognitive decline in SVD, which is in line with earlier findings. These findings suggests that in our study sample network efficiency measures are the most suitable surrogate markers for cognitive performance in patients with cerebral SVD among all network measures and MRI markers, and play a key role in the genesis of cognitive decline in SVD.

Longitudinal changes in rich club organization and cognition in cerebral small vessel disease.

Cerebral small vessel disease (SVD) is considered the most important vascular contributor to the development of cognitive impairment and dementia. There is increasing awareness that SVD exerts its clinical effects by disrupting white matter connections, predominantly disrupting connections between rich club nodes, a set of highly connected and interconnected regions. Here we examined the progression of disturbances in rich club organization in older adults with SVD and their associations with conventional SVD markers and cognitive decline. We additionally investigated associations of baseline network measures with dementia. In 270 participants of the RUN DMC study, we performed diffusion tensor imaging (DTI) and cognitive assessments longitudinally. Rich club organization was examined in structural networks derived from DTI followed by deterministic tractography. Global efficiency (p<0.05) and strength of rich club connections (p<0.001) declined during follow-up. Decline in strength of peripheral connections was associated with a decline in overall cognition (ß=0.164; p<0.01), psychomotor speed (ß=0.151; p<0.05) and executive function (ß=0.117; p<0.05). Baseline network measures were reduced in participants with dementia, and the association between WMH and dementia was causally mediated by global efficiency (p = =0.037) and peripheral connection strength (p = =0.040). SVD-related disturbances in rich club organization progressed over time, predominantly in participants with severe SVD. In this study, we found no specific role of rich club connectivity disruption in causing cognitive decline or dementia. The effect of WMH on dementia was mediated by global network efficiency and the strength of peripheral connections, suggesting an important role for network disruption in causing cognitive decline and dementia in older adults with SVD.

The role of small diffusion-weighted imaging lesions in cerebral small vessel disease.

OBJECTIVE: To investigate the prevalence of asymptomatic diffusion-weighted imaging-positive (DWI+) lesions in individuals with cerebral small vessel disease (SVD) and identify their role in the origin of SVD markers on MRI. METHODS: We included 503 individuals with SVD from the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Imaging Cohort (RUN DMC) study (mean age 65.6 years [SD 8.8], 56.5% male) with 1.5T MRI in 2006 and, if available, follow-up MRI in 2011 and 2015. We screened DWI scans (n = 1,152) for DWI+ lesions, assessed lesion evolution on follow-up fluid-attenuated inversion recovery, T1 and T2* images, and examined the association between DWI+ lesions and annual SVD progression (white matter hyperintensities [WMH], lacunes, microbleeds). RESULTS: We found 50 DWI+ lesions in 39 individuals on 1,152 DWI (3.4%). Individuals with DWI+ lesions were older (p = 0.025), more frequently had a history of hypertension (p = 0.021), and had a larger burden of preexisting SVD MRI markers (WMH, lacunes, microbleeds: all p < 0.001) compared to individuals without DWI+ lesions. Of the 23 DWI+ lesions with available follow-up MRI, 14 (61%) evolved into a WMH, 8 (35%) resulted in a cavity, and 1 (4%) was no longer visible. Presence of DWI+ lesions was significantly associated with annual WMH volume increase and yearly incidence of lacunes and microbleeds (all p < 0.001). CONCLUSION: Over 3% of individuals with SVD have DWI+ lesions. Although DWI+ lesions play a role in the progression of SVD, they may not fully explain progression of SVD markers on MRI, suggesting that other factors than acute ischemia are at play.

Cognitive consequences of regression of cerebral small vessel disease.

INTRODUCTION: Recent studies have shown that neuroimaging markers of cerebral small vessel disease can also regress over time. We investigated the cognitive consequences of regression of small vessel disease markers. PATIENTS AND METHODS: Two hundred and seventy-six participants of the RUNDMC study underwent neuroimaging and cognitive assessments at three time-points over 8.7 years. We semi-automatically assessed white matter hyperintensities volumes and manually rated lacunes and microbleeds. We analysed differences in cognitive decline and accompanying brain atrophy between participants with regression, progression and stable small vessel disease by analysis of variance. RESULTS: Fifty-six participants (20.3%) showed regression of small vessel disease markers: 31 (11.2%) white matter hyperintensities regression, 10 (3.6%) vanishing lacunes and 27 (9.8%) vanishing microbleeds. Participants with regression showed a decline in overall cognition, memory, psychomotor speed and executive function similar to stable small vessel disease. Participants with small vessel disease progression showed more cognitive decline compared with stable small vessel disease (p < 0.001 for cognitive index and memory; p < 0.01 for executive function), although significance disappeared after adjusting for age and sex. Loss of total brain, gray matter and white matter volume did not differ between participants with small vessel disease regression and stable small vessel disease, while participants with small vessel disease progression showed more volume loss of total brain and gray matter compared to those with stable small vessel disease (p < 0.05), although significance disappeared after adjustments. DISCUSSION: Regression of small vessel disease markers was associated with similar cognitive decline compared to stable small vessel disease and did not accompany brain atrophy, suggesting that small vessel disease regression follows a relatively benign clinical course. Future studies are required to validate these findings and to assess the role of vascular risk factor control on small vessel disease regression and possible recovery of clinical symptoms. CONCLUSION: Our findings of comparable cognitive decline between participants with regression and stable small vessel disease might suggest that small vessel disease regression has a relative benign cognitive outcome.

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: ß = .067; 95%CI[.024-0.111]; p < .01; EM: ß = .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 (ß = -.170; p = .001) and hippocampal atrophy (ß = 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.

Brain atrophy and strategic lesion location increases risk of parkinsonism in cerebral small vessel disease.

INTRODUCTION: Incident parkinsonism in patients with comparable cerebral small vessel disease (SVD) burden is not fully explained by presence of SVD alone. We therefore investigated if severity of SVD, SVD location, incidence of SVD and/or brain atrophy plays a role in this distinct development of parkinsonism. METHODS: Participants were from the RUN DMC study, a prospective cohort of 503 individuals with SVD. Parkinsonism was diagnosed according to the UKPDS brain bank criteria. Fine and Gray method was used to assess the association between SVD and incident parkinsonism. Differences in white matter hyperintensities (WMH) progression and brain atrophy were calculated with a linear mixed effect analysis. RESULTS: After a median follow-up of 8.6 years, 32 of 501 participants developed parkinsonism (6.4%). The highest WMH load was found in the frontal lobe for both groups. Presence of more than one lacune at baseline was higher in the group who developed parkinsonism, especially in the frontal lobe (22% versus 3%, p < 0.001) and basal ganglia (12.5% versus 1%, p-value <0.001). The annual rate of total brain atrophy was significantly higher for those who developed parkinsonism compared to those who did not (8.7 ml [95%CI 7.1-10.3] and 4.9 ml [95%CI 4.5-5.3], respectively). While WMH progression was not different, incidence of lacunes and microbleeds was higher in the group with parkinsonism. CONCLUSION: The risk of parkinsonism in patients with SVD is especially increased when WMH and lacunes are present in the frontal lobe. A higher brain atrophy rate might further increase this risk.

Risk of Nursing Home Admission in Cerebral Small Vessel Disease.

Background and Purpose- Since cerebral small vessel disease (SVD) is associated with cognitive and motor impairment and both might ultimately lead to nursing home admission, our objective was to investigate the association of SVD markers with nursing home admission. Methods- The RUN DMC study (Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort) is a prospective cohort of 503 independent living individuals with SVD. Date of nursing home admission was retrieved from the Dutch municipal personal records database. Risk of nursing home admission was calculated using a competing risk analysis, with mortality as a competing risk. Results- During follow-up (median 8.7 years, interquartile range 8.5-8.9), 31 participants moved to a nursing home. Before nursing home admission, 19 participants were diagnosed with dementia, 6 with parkinsonism, and 10 with stroke. Participants with the lowest white matter volume had an 8-year risk of nursing home admission of 13.3% (95% CI, 8.6-18.9), which was significantly different from participants with middle or highest white matter volume (respectively, 4.8% [95% CI, 2.3-8.8] and 0%; P<0.001). After adjusting for baseline age and living condition, the association of white matter volume and total brain volume with nursing home admission was significant, with, respectively, hazard ratios of 0.88 [95% CI, 0.84-0.95] ( P value 0.025) and 0.92 [95% CI, 0.85-0.98] ( P<0.001) per 10 mL. The association of white matter hyperintensities and lacunes with nursing home admission was not significant. Conclusions- This study demonstrates that in SVD patients, independent from age and living condition, a lower white matter volume and a lower total brain volume is associated with an increased risk of nursing home admission. Nursing home admission is a relevant outcome in SVD research since it might be able to combine both cognitive and functional consequences of SVD in 1 outcome.

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 Aß (Amyloid-ß) 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 Aß (amyloid ß) levels may be useful as early biomarker, but the role of plasma Aß in SVD remains to be elucidated. We investigated the association of plasma Aß 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 Aß38, Aß40, and Aß42 levels using ELISAs. We longitudinally assessed volume of white matter hyperintensities semiautomatically and manually rated lacunes and microbleeds. We analyzed associations between plasma Aß and SVD markers by ANCOVA adjusted for age, sex, and hypertension. RESULTS: Cross-sectionally, plasma Aß40 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 Aß38 and Aß40 were elevated in participants with severe white matter hyperintensities (Aß38, 25.3 versus 22.7 pg/mL; P<0.01; Aß40, 201.8 versus 183.3 pg/mL; P<0.05). Longitudinally, plasma Aß40 levels were elevated in participants with white matter hyperintensity progression (mean, 194.6 versus 182.9 pg/mL; P<0.05). Both Aß38 and Aß40 were elevated in participants with incident lacunes (Aß38, 24.5 versus 22.5 pg/mL; P<0.05; Aß40, 194.9 versus 181.2 pg/mL; P<0.01) and Aß42 in participants with incident microbleeds (62.8 versus 60.4 pg/mL; P<0.05). CONCLUSIONS: Plasma Aß levels are associated with both presence and progression of SVD markers, suggesting that Aß pathology might contribute to the development and progression of SVD. Plasma Aß levels might thereby serve as inexpensive and noninvasive measure for identifying individuals with increased risk for progression of SVD.

Clinical correlates of cerebral white matter abnormalities in patients with Parkinson's disease.

OBJECTIVE: To determine if autonomic dysfunction, cognitive disorders or axial disability are associated with white matter lesions (WML) in Parkinson disease (PD). METHODS: We performed a retrospective cross-sectional review study on 204 consecutive PD patients who underwent cerebral MRI in our center between January 2012 and July 2016. For each patient, we scored the severity of WML and PV (periventricular) WML using the Fazekas score and using the ARWMC scale for WML and BG (basal ganglia) and clinical characteristics such as neurogenic orthostatic hypotension and cognitive function. RESULTS: 204 PD patients were included of whom n = 53 (26.0%) had neurogenic orthostatic hypotension (nOH). The presence of nOH was significantly associated with the severity of WML as defined by the Fazekas score and the ARWMC scale. An ordinal regression model confirmed this association with an OR of 0.41 (95% CI 0.18-0.92: p = .03) and an OR of 0.39 (95% CI 0.17-0.88: p = .02). There were no significant associations between WML and other co-variables, including hypertension, dopaminergic medication use, Hoehn and Yahr stage, gender and cognitive decline. CONCLUSION: The presence of nOH is associated with WML severity in PD patients.

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.