Protocol: The Lacunar Intervention Trial 2 (LACI-2). A trial of two repurposed licenced drugs to prevent progression of cerebral small vessel disease

Background Small vessel disease causes a quarter of ischaemic strokes (lacunar subtype), up to 45% of dementia either as vascular or mixed types, cognitive impairment and physical frailty. However, there is no specific treatment to prevent progression of small vessel disease. Aim We designed the LACunar Intervention Trial-2 (LACI-2) to test feasibility of a large trial testing cilostazol and/or isosorbide mononitrate (ISMN) by demonstrating adequate participant recruitment and retention in follow-up, drug tolerability, safety and confirm outcome event rates required to power a phase 3 trial. Methods and design LACI-2 is an investigator-initiated, prospective randomised open label blinded endpoint (PROBE) trial aiming to recruit 400 patients with prior lacunar syndrome due to a small subcortical infarct. We randomise participants to cilostazol v no cilostazol and ISMN or no ISMN, minimising on key prognostic factors. All patients receive guideline-based best medical therapy. Patients commence trial drug at low dose, increment to full dose over 2–4 weeks, continuing on full dose for a year. We follow-up participants to one year for symptoms, tablet compliance, safety, recurrent vascular events, cognition and functional outcomes, Trails B and brain MRI. LACI-2 is registered ISRCTN 14911850, EudraCT 2016–002277-35. Trial outcome: Primary outcome is feasibility of recruitment and compliance; secondary outcomes include safety (cerebral or systemic bleeding, falls, death), efficacy (recurrent cerebral and cardiac vascular events, cognition on TICS, Trails B) and tolerability. Summary LACI-2 will determine feasibility, tolerability and provide outcome rates to power a large phase 3 trial to prevent progression of cerebral small vessel disease.

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Risk of vascular events in different manifestations of cerebral small vessel disease: A 2-year follow-up study with a control group

Heliyon ◽

10.1016/j.heliyon.2017.e00455 ◽

2017 ◽

Vol 3 (11) ◽

pp. e00455 ◽

Cited By ~ 6

Author(s):

Jacek Staszewski ◽

Renata Piusińska-Macoch ◽

Bogdan Brodacki ◽

Ewa Skrobowska ◽

Katarzyna Macek ◽

...

Keyword(s):

Small Vessel Disease ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Control Group ◽

Vascular Events ◽

Vessel Disease ◽

Follow Up Study

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Abstract TMP119: High Homocysteine Level is not Associated With White Matter Changes, Dementia nor Mortality After Ischemic Stroke

Stroke ◽

10.1161/str.47.suppl_1.tmp119 ◽

2016 ◽

Vol 47 (suppl_1) ◽

Author(s):

Susanna Melkas ◽

Sami Curtze ◽

Gerli Sibolt ◽

Niku K Oksala ◽

Jukka Putaala ◽

...

Keyword(s):

Ischemic Stroke ◽

White Matter ◽

Homocysteine Level ◽

Small Vessel Disease ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Cross Sectional ◽

White Matter Changes ◽

Vessel Disease

Background: Association between high homocysteine level and cerebral small-vessel disease has been implicated in cross-sectional studies, but results from longitudinal studies have been less clear. The aim of this study was to investigate whether homocysteine level at 3-months poststroke relates to the occurrence of white matter changes (WMC), the surrogate of cerebral small-vessel disease. We also investigated whether it relates to the prognosis after ischemic stroke regarding the risk of dementia at 3-months and mortality in long-term follow-up. Methods: A total of 321 consecutive acute ischemic stroke patients aged 55 to 85 were included in the study and followed up to 12 years. Plasma homocysteine level and occurrence of WMC in MRI were measured 3 months poststroke and dementia according to DSM-III was evaluated at the same time. Findings: The median homocysteine level was 13.50 μmol/l (interquartile range [IQR] 10.60-18.50 μmol/l). Total of 81 patients (25.2%) had homocysteine level above 18.50 μmol/l. In logistic regression analysis, homocysteine level above 18.50 μmol/l was not associated with severe WMC nor with dementia at 3 months poststroke. In Kaplan-Meier analysis, homocysteine level above 18.50 μmol/l was not associated with survival in 12-year follow-up. For further analysis, the group was divided in quartiles according to homocysteine level. The quartiles did not differ in occurrence of severe WMC at baseline, in the risk of dementia at 3 months, nor in the risk of mortality in 12-year follow-up. Interpretation: In our poststroke cohort homocysteine level is not associated with WMC. Further, it does not relate to impaired prognosis manifested as dementia at 3 months or mortality in 12-year follow-up.

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Total Cerebral Small Vessel Disease Burden Is Related to Worse Performance on the Mini-Mental State Examination and Incident Dementia: A Prospective 5-Year Follow-Up

Journal of Alzheimer s Disease ◽

10.3233/jad-181135 ◽

2019 ◽

Vol 69 (1) ◽

pp. 253-262 ◽

Cited By ~ 8

Author(s):

Yanfeng Jiang ◽

Yingzhe Wang ◽

Ziyu Yuan ◽

Kelin Xu ◽

Kexun Zhang ◽

...

Keyword(s):

Mental State ◽

Disease Burden ◽

Mini Mental State Examination ◽

Small Vessel Disease ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Vessel Disease ◽

Incident Dementia ◽

State Examination

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Nonlinear temporal dynamics of cerebral small vessel disease

Neurology ◽

10.1212/wnl.0000000000004490 ◽

2017 ◽

Vol 89 (15) ◽

pp. 1569-1577 ◽

Cited By ~ 35

Author(s):

Esther M.C. van Leijsen ◽

Ingeborg W.M. van Uden ◽

Mohsen Ghafoorian ◽

Mayra I. Bergkamp ◽

Valerie Lohner ◽

...

Keyword(s):

Temporal Dynamics ◽

Diffusion Tensor ◽

Small Vessel Disease ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Quadratic Term ◽

Vessel Disease ◽

Semiautomatic Segmentation ◽

Over Time

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.

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Serum neurofilament light is sensitive to active cerebral small vessel disease

Neurology ◽

10.1212/wnl.0000000000004645 ◽

2017 ◽

Vol 89 (20) ◽

pp. 2108-2114 ◽

Cited By ~ 49

Author(s):

Thomas Gattringer ◽

Daniela Pinter ◽

Christian Enzinger ◽

Thomas Seifert-Held ◽

Markus Kneihsl ◽

...

Keyword(s):

Single Molecule ◽

Small Vessel Disease ◽

Brain Mri ◽

Cerebral Small Vessel Disease ◽

Community Dwelling ◽

Small Vessel ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Vessel Disease

Objective:To explore whether serum neurofilament light chain protein (NfL) levels are increased in patients with MRI-confirmed recent small subcortical infarcts (RSSI) compared to healthy controls and to determine the subsequent course and determinants of NfL levels in a longitudinal manner.Methods:In a prospectively collected group of symptomatic patients with an RSSI (n = 79, mean age 61 ± 11 years, 67% male), we analyzed brain MRI and serum NfL using a Single Molecule Array (Simoa) assay at baseline and at 3 and 15 months after stroke. Community-dwelling healthy age- and sex-matched individuals with comparable severity of MRI white matter hyperintensities (WMH) (n = 53) served as controls.Results:Patients with an RSSI had higher NfL baseline levels compared to controls (73.45 vs 34.59 pg/mL, p < 0.0001), and they were increasingly higher with the time from stroke symptom onset to blood sampling (median 4 days, range 1–11 days, rs = 0.51, p < 0.0001). NfL levels remained increased at the 3-month follow-up but returned to normal at 15 months after stroke. NfL levels were associated with RSSI size and baseline WMH severity and were especially high in patients with new, clinically silent cerebral small vessel disease (CSVD)–related lesions at follow-up.Conclusions:Serum NfL is increased in patients with an RSSI and the occurrence of new CSVD-related MRI lesions, even when clinically silent. This suggests NfL as a blood biomarker for active CSVD.

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Total Cerebral Small-Vessel Disease Score is Associated with Mortality during Follow-Up after Acute Ischemic Stroke

Journal of Clinical Neurology ◽

10.3988/jcn.2017.13.2.187 ◽

2017 ◽

Vol 13 (2) ◽

pp. 187 ◽

Cited By ~ 29

Author(s):

Tae-Jin Song ◽

Jinkwon Kim ◽

Dongbeom Song ◽

Joonsang Yoo ◽

Hye Sun Lee ◽

...

Keyword(s):

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Small Vessel Disease ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Disease Score ◽

Vessel Disease

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Serum Neurofilament Light Chain Is Associated with Incident Lacunes in Progressive Cerebral Small Vessel Disease

Journal of Stroke ◽

10.5853/jos.2019.02845 ◽

2020 ◽

Vol 22 (3) ◽

pp. 369-376

Author(s):

Nils Peters ◽

Esther van Leijsen ◽

Anil M. Tuladhar ◽

Christian Barro ◽

Marek J. Konieczny ◽

...

Keyword(s):

Cognitive Impairment ◽

Small Vessel Disease ◽

Cerebral Small Vessel Disease ◽

Analysis Of Covariance ◽

Small Vessel ◽

Cognitive Measures ◽

Neurofilament Light ◽

Baseline Serum ◽

Vessel Disease

Background and Purpose Serum neurofilament light (NfL)-chain is a circulating marker for neuroaxonal injury and is also associated with severity of cerebral small vessel disease (SVD) cross-sectionally. Here we explored the association of serum-NfL with imaging and cognitive measures in SVD longitudinally.Methods From 503 subjects with SVD, baseline and follow-up magnetic resonance imaging (MRI) was available for 264 participants (follow-up 8.7±0.2 years). Baseline serum-NfL was measured by an ultrasensitive single-molecule-assay. SVD-MRI-markers including white matter hyperintensity (WMH)-volume, mean diffusivity (MD), lacunes, and microbleeds were assessed at both timepoints. Cognitive testing was performed in 336 participants, including SVD-related domains as well as global cognition and memory. Associations with NfL were assessed using linear regression analyses and analysis of covariance (ANCOVA).Results Serum-NfL was associated with baseline WMH-volume, MD-values and presence of lacunes and microbleeds. SVD-related MRI- and cognitive measures showed progression during follow-up. NfL-levels were associated with future MRI-markers of SVD, including WMH, MD and lacunes. For the latter, this association was independent of baseline lacunes. Furthermore, NfL was associated with incident lacunes during follow-up (P=0.040). NfL-levels were associated with future SVD-related cognitive impairment (processing speed: β=–0.159; 95% confidence interval [CI], –0.242 to –0.068; P=0.001; executive function β=–0.095; 95% CI, –0.170 to –0.007; P=0.033), adjusted for age, sex, education, and depression. Dementia-risk increased with higher NfL-levels (hazard ratio, 5.0; 95% CI, 2.6 to 9.4; P<0.001), however not after adjusting for age.Conclusions Longitudinally, serum-NfL is associated with markers of SVD, especially with incident lacunes, and future cognitive impairment affecting various domains. NfL may potentially serve as an additional marker for disease monitoring and outcome in SVD, potentially capturing both vascular and neurodegenerative processes in the elderly.

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Periodic Limb Movements Syndrome in Patients With Cerebral Small Vessel Disease: Protocol for a Prospective Observational Study

Frontiers in Neurology ◽

10.3389/fneur.2021.700151 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ekaterina Spektor ◽

Ingo Fietze ◽

Mikhail G. Poluektov

Keyword(s):

Cognitive Decline ◽

Small Vessel Disease ◽

Brain Mri ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Periodic Limb Movements ◽

Apnea Hypopnea Index ◽

Limb Movements ◽

Vessel Disease

Background: Cerebrovascular diseases are the leading cause of cognitive decline and dementia. Therefore, the investigation of the potential ways to slow down the disease progression is an important research field. Periodic limb movements in sleep (PLMS) are known to be associated with transient changes in heart rate and blood pressure. These changes might influence the course of cerebral small vessel disease (cSVD). Nevertheless, the clinical significance of PLMS, particularly its influence on cardiovascular diseases course, is still controversial and underinvestigated.Methods/design: Patients from 60 to 75 years old diagnosed with cSVD will undergo nocturnal polysomnography. Subjects with apnea/hypopnea index under 5 will be enrolled. Sleep quality and daytime functioning will be assessed at baseline with self-reported questionnaires. Brain MRI and cognitive assessment will be performed at baseline and in the 2-year follow-up. Progression of cSVD markers and cognitive dysfunction will be compared between patients with PLMS index (PLMI) equal to or more than 15 movements per hour of sleep and controls (PLMI <15/h).Discussion: The negative role of PLMS in cSVD progression and related cognitive decline is expected. We suppose that patients with PLMS tend to worsen in cognitive performance more rapidly than age-, gender-, and comorbidity-matched controls. We also expect them to have more rapid white matter hyperintensities and other cSVD marker progression. The limitations of the study protocol are the short follow-up period, the absence of a treatment group, and inability to make a conclusion about causality.

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Association of total cerebral small vessel disease burden with the cavitation of recent small subcortical infarcts

Acta Radiologica ◽

10.1177/02841851211066583 ◽

2021 ◽

pp. 028418512110665

Author(s):

Meimei Wang ◽

Yunfei Li ◽

Yingjie Song ◽

Yingyu Zhao ◽

Xiaohu Zhao

Keyword(s):

White Matter ◽

White Matter Hyperintensities ◽

Small Vessel Disease ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Perivascular Spaces ◽

Vessel Disease ◽

Multivariable Regression ◽

Total Burden

Background Recent small subcortical infarcts (RSSIs) could evolve into cavitation (lacunes) or non-cavitation (white matter hyperintensities or disappearance) during the chronic period, but the factors involved remain unclear. Purpose To explore the association between total cerebral small vessel disease (CSVD) burden and lesion cavitation. Material and Methods We retrospectively selected 202 inpatients with an isolated RSSI who underwent baseline and follow-up magnetic resonance imaging (median interval = 16.6 months; interquartile range [IQR]=8.2–30.1). Inpatients were divided into cavitation and non-cavitation groups depending on whether a fluid-filled cavity formed. Data including demographic, clinical, and radiological features were collected and analyzed. To determine total CSVD burden, four imaging markers, including lacunes, microbleeds, white matter hyperintensities, and enlarged perivascular spaces, were rated and summed as a final practical score between 0 and 4. Results Overall, 137 (67.8%) patients progressed to cavitation and 65 (32.2%) to non-cavitation. Binary multivariable regression analysis showed that the baseline total CSVD burden ( P = 0.005) and infarct diameter ( P = 0.002) were independent risk factors for cavitation. A severe total burden (scores of 3–4) at baseline was independently related to cavitation ( P = 0.001). Moreover, the total CSVD burden score varied from 2 (IQR=1–3) at baseline to 3 (IQR=2–4) at follow-up. The extent of the increase in total burden was correlated with cavitation ( r = 0.201; P = 0.004). Conclusion Total CSVD burden, both the baseline value and extent of increase, was positively associated with cavitation. RSSIs with severe total CSVD burden at baseline have a greater potential to become cavitated.

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