Are central and systemic inflammation associated with fatigue in cerebral small vessel disease?

BACKGROUND: Fatigue is a common symptom in cerebral small vessel disease (SVD), but its pathogenesis is poorly understood. It has been suggested that inflammation may play a role. We determined whether central (neuro) inflammation and peripheral inflammation were associated with fatigue in SVD. METHODS: Notably, 36 patients with moderate-to-severe SVD underwent neuropsychometric testing, combined positron emission tomography and magnetic resonance imaging (PET-MRI) scan, and blood draw for the analysis of inflammatory blood biomarkers. Microglial signal was taken as a proxy for neuroinflammation, assessed with radioligand 11C-PK11195. Of these, 30 subjects had full PET datasets for analysis. We assessed global 11C-PK11195 binding and hotspots of 11C-PK11195 binding in the normal-appearing white matter, lesioned tissue, and combined total white matter. Peripheral inflammation was assessed with serum C-reactive protein (CRP) and using the Olink cardiovascular III proteomic panel comprising 92 biomarkers of cardiovascular inflammation and endothelial activation. Fatigue was assessed using the fatigue severity scale (FSS), the visual analog fatigue scale, and a subscale of the Geriatric Depression Scale. RESULTS: Mean (SD) age was 68.7 (11.2) years, and 63.9% were male. Of these, 55.6% showed fatigue on the FSS. Fatigued participants had higher disability scores (p = 0.02), higher total GDS scores (p = 0.02), and more commonly reported a history of depression (p = 0.04). 11C-PK11195 ligand binding in the white matter was not associated with any measure of fatigue. Serum CRP was significantly associated with average fatigue score on FSS (ρ = 0.48, p = 0.004); this association persisted when controlling for age, sex, disability score, and depression (ß = 0.49, 95% CI (0.17, 2.26), p = 0.03). Blood biomarkers from the Olink panel showed no association with fatigue. CONCLUSION: In symptomatic SVD patients, neuroinflammation, assessed with microglial marker 11C-PK11195, was not associated with fatigue. We found some evidence for a role of systematic inflammation, evidenced by an association between fatigue severity and raised CRP, but further studies are required to understand this relationship and inform whether it could be therapeutically modified to reduce fatigue severity. DATA ACCESS STATEMENT: Data for this study are available from the corresponding author upon reasonable request.

Apathy After Stroke: Incidence, Symptom Trajectory, and Impact on Quality of Life and Disability

BACKGROUND AND OBJECTIVES: Apathy is one of the most common symptoms following stroke and is often associated with worse functional outcome and poor quality of life (QoL). The trajectory of apathy symptoms has been previously described, and different trajectories have been identified. We determined group and individual changes in apathy symptomatology from the acute phase until 1 year after stroke. We also examined the association of apathy and depression with disability and QoL 1 year after stroke. METHODS: We measured apathy in a cohort of ischemic stroke survivors at 4 time points from 0 to 12 months after stroke. The Apathy Evaluation Scale (AES) and Dimensional Apathy Scale (DAS) were administered at each time point. Where possible we obtained apathy measured from carers. Depression was assessed with the Geriatric Depression Scale (GDS). Disability and QoL were assessed with the modified Rankin Scale (mRS) and 36-Item Short Form Survey (SF-36). We examined the cross-sectional and individual trajectory of apathy symptoms in each dimension and looked at associations of apathy and depression soon after stroke with mRS and SF-36 at 1 year. RESULTS: Of 200 participants enrolled, 165 completed apathy measures at 12 months. Patient-rated apathy scores increased in both tests at the group level (AES: χ2(3) = 9.86, p = 0.019; DAS: χ2(3) = 8.49, p = 0.037) and individual level (AES: ß = 0.13, p = 0.002; DAS ß = 0.13, p = 0.005; DAS: executive ß = 0.08, p < 0.001). By contrast, carer-rated apathy did not significantly increase (AES: χ2(3) = 0.75, p = 0.862; DAS: χ2(3) = 2.45, p = 0.484). Apathy scores were associated with worse mRS and SF-36, although most associations were no longer significant when controlling for depression. GDS was associated with worse mRS and SF-36 after controlling for covariates and apathy (mRS: ß = 0.08, p = 0.006; SF-36 Mental Component Summary: ß = -1.53, p < 0.001; SF-36 Physical Component Summary: ß = -0.57, p = 0.016). DISCUSSION: Self-reported apathy progressively increases after stroke, especially in the executive dimension. Apathy is associated with worse QoL and greater disability, although some of these associations might be mediated by depression.

Neuroimaging correlates of post-stroke fatigue: A systematic review and meta-analysis.

BACKGROUND: Fatigue is a common and disabling symptom following stroke, but its underlying mechanisms are unknown. Associations with a number of imaging features have been proposed. AIMS: We aimed to assess whether neuroimaging parameters could better inform our understanding of possible causes of post-stroke fatigue (PSF) through systematic review and meta-analysis. METHODS: Using a predefined protocol registered with PROSPERO (ID: CRD42022303168), we searched EMBASE, MEDLINE, PubMed, and PsycInfo for studies assessing PSF and computerized tomography (CT), magnetic resonance (MR), positron emission tomography (PET) imaging, or diffusion tensor imaging (DTI). We extracted neuroimaging parameters and narratively analyzed study results to assess any association with PSF. Where there were 3+ similar studies, we carried out a meta-analysis using inverse-variance random-effects model to estimate the total association of each neuroimaging parameter on PSF. The risk of bias was assessed using the Newcastle and Ottawa Scale. RESULTS: We identified 46 studies (N = 6543); in many studies, associations with fatigue were secondary or subanalyses (28.3%). Imaging parameters were assessed across eight variables: lesion lateralization, lesion location, lesion volume, brain atrophy, infarct number, cerebral microbleeds, white matter hyperintensities (WMHs), and network measures. Most variables showed no conclusive evidence for any association with fatigue. Meta-analysis, where possible, showed no association of the following with PSF; left lesion lateralization (OR: 0.88, 95% CI (0.64, 1. 22) (p = 0.45)), infratentorial lesion location (OR: 1.83, 95% CI (0.63, 5.32) (p = 0.27)), and WMH (OR: 1.21, 95% CI (0.84, 1.75) (p = 0.29)). Many studies assessed lesion location with mixed findings; only one used voxel-symptom lesion-mapping (VSLM). Some small studies suggested an association between altered functional brain networks, namely frontal, fronto-striato-thalamic, and sensory processing networks, with PSF. CONCLUSION: There was little evidence for the association between any neuroimaging parameters and PSF. Future studies should utilize advanced imaging techniques to fully understand the role of lesion location in PSF, while the role of altered brain networks in mediating PSF merits further research.

Aging effects on extrapersonal (far-space) attention: cancellation and line bisection performance from 179 healthy adults.

Assessment of cognitive impairments is a vital part of clinical practice. Cancellation (visual search) and line bisection are commonly used tasks to assess visuospatial attention. Despite the fact visuospatial attention is engaged in both near (within reach) and far-space (out of reach), most studies have been conducted in near-space alone. Moreover, despite their use in clinical practice, it is unclear whether cancellation and bisection tasks are related. Here, we investigated the impact of aging on cancellation and line bisection performance in far-space in a large healthy sample. We provide preliminary age-graded norms for assessing visuospatial attention in far-space calculated from a sample of 179 healthy adults, between the ages of 18-94 (mean age = 49.29). Cancellation and line bisection were presented on a large screen in far-space and completed using a wireless remote. Aging was accompanied by longer task duration for both tasks, slower search speed and poorer quality of search. However, there was no significant effect of aging on line bisection error. There was a significant correlation between the two tasks in that longer task duration in line bisection was associated with slower search speed and poorer quality of search. Overall, participants presented a leftward bias during cancellation and line bisection akin to pseudoneglect. Moreover, we found that irrespective of age, search speed was faster in males than females. We offer novel evidence that performance on cancellation and line bisection tasks are related to one another in far-space, but are also sensitive to age-related decline, and even sex differences.

Association of NOTCH3 Variant Position With Stroke Onset and Other Clinical Features Among Patients With CADASIL.

BACKGROUND AND OBJECTIVES: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by a cysteine-altering mutation in one of the thirty-four epidermal growth factor-like repeat (EGFR) domains of the NOTCH3 protein. CADASIL has a variable phenotypic presentation and NOTCH3 mutations in EGFRs 1-6 have been found correlated with greater disease severity. We examined clinical and radiological features and performed bioinformatic annotation of mutations in a large CADASIL cohort to further understand these associations. METHODS: We examined the association of NOTCH3 variant position on stroke onset and other clinical features among patients with CADASIL from the United Kingdom. We also explored how in-silico predicted protein aggregation differed by variant position and the extent to which this affected stroke risk. RESULTS: We identified 76 different cysteine-altering NOTCH3 variants in our cohort of 485 patients (mean age: 50.1 years; % male: 57.5). After controlling for cardiovascular risk factors, variants in EGFRs 1-6 were associated with earlier onset of stroke (hazard ratio [HR]: 2.05, 95% CI: 1.43-2.94) and encephalopathy (HR: 2.70, 95% CI: 1.15-6.37), than variants in EGFRs 7-34. Although the risk of stroke was higher in the patients with predicted protein aggregation (HR: 1.50, 95% CI: 1.05-2.14), this association was no longer significant after controlling for variant site. Further analysis suggested lower stroke risk was observed for variants in EGFRs 10-17 compared to variants in the other EGFR domains. DISCUSSION: NOTCH3 variant position is a predictor of stroke and encephalopathy in CADASIL independent of cardiovascular risk factors. Lower stroke risk was found for variants in EGFRs 10-17. Molecular factors that influence CADASIL disease severity remain to be determined.

Prevalence and Predictors of Vascular Cognitive Impairment in Patients With CADASIL.

BACKGROUND AND OBJECTIVE: CADASIL is the most common monogenic form of stroke and early onset dementia. We determined the prevalence of vascular cognitive impairment (VCI) in a cohort of CADASIL patients, and investigated which factors were associated with VCI risk, including clinical, genetic and MRI parameters. METHODS: Cognition was assessed in genetically confirmed CADASIL patients (n = 176) and healthy controls (n = 265) (mean(SD) age 50.95(11.35) v 52.37(7.93) years), using the Brief Memory and Executive Test (BMET) and the Montreal Cognitive Assessment (MoCA). VCI was defined according to previously validated cut-offs. We determined the prevalence of VCI and its associations with clinical risk factors, mutation location (EGFr 1-6 versus EGFr 7-34), and MRI markers of small vessel disease. RESULTS: VCI was more common in CADASIL than controls; 39.8 v 10.2% on BMET 47.7% v 19.6% of MOCA. CADASIL patients had worse performance across all cognitive domains. History of stroke was associated with VCI on the BMET (OR 2.12, 95% CI [1.05, 4.27] p = 0.04) and on the MoCA (OR 2.55 [1.21, 5.41] p = 0.01), after controlling for age and sex. There was no association of VCI with mutation site. Lacune count was the only MRI parameter independently associated with VCI on the BMET (OR: 1.63, 95% CI [1.10, 2.41], p = 0.014), after controlling for other MRI parameters. These associations persisted after controlling for education in the sensitivity analyses. CONCLUSIONS: VCI is present in almost half of CADASIL patients with a mean age of 50. Stroke and lacune count on MRI were both independent predictors of VCI on the BMET.