Table1_Attenuated inflammatory profile following single and repeated handgrip exercise and remote ischemic preconditioning in patients with cerebral small vessel disease.XLSX

Background: Similar to remote ischemic preconditioning bouts of exercise may possess immediate protective effects against ischemia-reperfusion injury. However, underlying mechanisms are largely unknown. This study compared the impact of single and repeated handgrip exercise versus remote ischemic preconditioning on inflammatory biomarkers in patients with cerebral small vessel disease (cSVD).Methods: In this crossover study, 14 patients with cSVD were included. All participants performed 4-day of handgrip exercise (4x5-minutes at 30% of maximal handgrip strength) and remote ischemic preconditioning (rIPC; 4x5-minutes cuff occlusion around the upper arm) twice daily. Patients were randomized to start with either handgrip exercise or rIPC and the two interventions were separated by > 9 days. Venous blood was drawn before and after one intervention, and after 4-day of repeated exposure. We performed a targeted proteomics on inflammation markers in all blood samples.Results: Targeted proteomics revealed significant changes in 9 out of 92 inflammatory proteins, with four proteins demonstrating comparable time-dependent effects between handgrip and rIPC. After adjustment for multiple testing we found significant decreases in FMS-related tyrosine kinase-3 ligand (Flt3L; 16.2% reduction; adjusted p-value: 0.029) and fibroblast growth factor-21 (FGF-21; 32.8% reduction adjusted p-value: 0.029) after single exposure. This effect did not differ between handgrip and rIPC. The decline in Flt3L after repeated handgrip and rIPC remained significant (adjusted p-value = 0.029), with no difference between rIPC and handgrip (adjusted p-value = 0.98).Conclusion: Single handgrip exercise and rIPC immediately attenuated plasma Flt3L and FGF-21, with the reduction of Flt3L remaining present after 4-day of repeated intervention, in people with cSVD. This suggests that single and repeated handgrip exercise and rIPC decrease comparable inflammatory biomarkers, which suggests activation of shared (anti-)inflammatory pathways following both stimuli. Additional studies will be needed to exclude the possibility that this activation is merely a time effect.</p

Flowchart study design.

<p>Flowchart study design.</p

Cumulative risks for epilepsy and epilepsy with recurrent seizures.

<p><b>A.</b> Overall cumulative risk. <b>B.</b> Cumulative risk according to stroke subtype. <b>C.</b> Cumulative risk according to gender.</p

Resting state functional connectivity of the default mode.

<p>Spatial maps of the default mode network for control subjects (A) and for stroke subjects (B). (C) Resting state functional connectivity differences between control and stroke subjects. Stroke subjects showed decreased functional connectivity in the posterior cingulate gyrus, medial prefrontal cortex and left medial temporal lobe. The statistical maps are superimposed onto the spatially normalized and averaged group T1-images.</p

Peak voxels for the default mode network component.

<p>Peak voxels of the regions for the independent component depicting the default mode network. These peak voxels were used for the region of interest (ROI) based analysis.</p>*<p>Left middle temporal gyrus was only significant at a lower threshold; this was obtained at a threshold of P<0.001 false-discovery rate (FDR) corrected. CS = Cluster size, R = Right, L = Left, MNI = Montreal Neurological Institute.</p

Recurrence of seizures according to time of onset first seizure.

*<p>early seizures are defined as occurring within the first week after the index event.</p>‡<p>late seizures are defined as occurring after the first week after the index event.</p>§<p><i>p-</i>value represents difference in incidence of recurrent seizures between patients with an initial first seizure versus patients with an initial late seizure, compared with chi-square.</p

Group analyses of the independent component analysis revealing seven distinct resting state networks (default mode, dorsal attention, auditory, frontal, sensorimotor lateral and medial visual network).

<p>Group analyses of the independent component analysis revealing seven distinct resting state networks (default mode, dorsal attention, auditory, frontal, sensorimotor lateral and medial visual network).</p

Cox proportional hazard.

*<p>epilepsy is defined as the occurrence of at least 1 seizure with an enduring cause.</p

Average power spectrum (± SEM) of the time course of the independent component that belongs to the default mode network is shown for both control and stroke subjects.

<p>The highest power density was observed in the low frequency domain (0.01–0.04 Hz) for both groups. No significant differences in frequency characteristics were observed between the control and stroke subjects.</p

Demographic and neuropsychological characteristics of stroke and control subjects.

<p>Values represent means (SD), median (range), or proportion (%). Stroke patients performed significantly worse on MMSE (p = 0.038) and CVLT-delayed recall score (p = 0.034). On other neuropsychological tests, no significant differences were found. Education score of 5 means 10–11 years of education. MMSE = Mini Mental State Examination, CVLT = California Verbal Learning Test, NIHSS = National Institutes of Health Stroke Scale. NA = not applicable.</p>a<p>Independent-samples t test.</p>b<p>Mann-Whitney test.</p>c<p>Chi-square analysis.</p