Severity of Small Vessel Disease Biomarkers Reduces the Magnitude of Cognitive Recovery after Ischemic Stroke.

OBJECTIVE: The objective of this study was to evaluate the impact of radiological biomarkers suggestive of cerebral small vessel disease (SVD) on the evolution of cognitive performances after an ischemic stroke (IS). METHODS: We studied patients with a supratentorial IS recruited consecutively to a prospective monocentric longitudinal study. A cognitive assessment was performed at baseline, 3 months, and 1 year and was based on a Montreal Cognitive Assessment, an Isaacs set test of verbal fluency (IST), and a Zazzo's cancellation task (ZCT) for the evaluation of attentional functions and processing speed. The following cerebral SVD biomarkers were detected on a 3-T brain MRI performed at baseline: white matter hyperintensities (WMHs), deep and lobar microbleeds, enlarged perivascular spaces in basal ganglia and centrum semiovale, previous small deep infarcts, and cortical superficial siderosis (cSS). Generalized linear mixed models were used to evaluate the relationship between these biomarkers and changes in cognitive performances. RESULTS: A total of 199 patients (65 ± 13 years, 68% male) were analyzed. Overall, the cognitive performances improved, more significantly in the first 3 months. Severe WMH was identified in 34% of the patients, and focal cSS in 3.5%. Patients with severe WMH and focal cSS had overall worse cognitive performances. Those with severe WMH had less improvement over time for IST (ß = -0.16, p = 0.02) and the number of errors to ZCT (ß = 0.19, p = 0.02), while those with focal cSS had less improvement over time for ZCT completion time (ß = 0.14, p = 0.01) and number of errors (ß = 0.17, p = 0.008), regardless of IS volume and location, gray matter volume, demographic confounders, and clinical and cardiovascular risk factors. CONCLUSION: The severity of SVD biomarkers, encompassing WMH and cSS, seems to reduce the magnitude of cognitive recovery after an IS. The detection of such SVD biomarkers early after stroke might help to identify patients with a cognitive vulnerability and a higher risk of poststroke cognitive impairment.

Normal-Appearing White Matter Integrity Is a Predictor of Outcome After Ischemic Stroke.

Background and Purpose- The aim of the present study was to evaluate the relationship between normal-appearing white matter (NAWM) integrity and postischemic stroke recovery in 4 main domains including cognition, mood, gait, and dependency. Methods- A prospective study was conducted, including patients diagnosed for an ischemic supratentorial stroke on a 3T brain MRI performed 24 to 72 hours after symptom onset. Clinical assessment 1 year after stroke included a Montreal Cognitive Assessment, an Isaacs set test, a Zazzo cancelation task, a Hospital Anxiety and Depression scale, a 10-meter walking test, and a modified Rankin Scale (mRS). Diffusion tensor imaging parameters in the NAWM were computed using FMRIB (Functional Magnetic Resonance Imaging of the Brain) Diffusion Toolbox. The relationships between mean NAWM diffusion tensor imaging parameters and the clinical scores were assessed using linear and ordinal regression analyses, including the volumes of white matter hyperintensities, gray matter, and ischemic stroke as radiological covariates. Results- Two hundred seven subjects were included (66±13 years old; 67% men; median National Institutes of Health Stroke Scale score, 3; interquartile range, 2-6). In the models including only radiological variables, NAWM fractional anisotropy was associated with the mRS and the cognitive scores. After adjusting for demographic confounders, NAWM fractional anisotropy remained a significant predictor of mRS (ß=-0.24; P=0.04). Additional path analysis showed that NAWM fractional anisotropy had a direct effect on mRS (ß=-0.241; P=0.001) and a less important indirect effect mediating white matter hyperintensity burden. Similar results were found with mean diffusivity, axial diffusivity, and radial diffusivity. In further subgroup analyses, a relationship between NAWM integrity in widespread white matter tracts, mRS, and Isaacs set test was found in right hemispheric strokes. Conclusions- NAWM diffusion tensor imaging parameters measured early after an ischemic stroke are independent predictors of functional outcome and may be additional markers to include in studies evaluating poststroke recovery.

Chronic Cortical Cerebral Microinfarcts Slow Down Cognitive Recovery After Acute Ischemic Stroke.

Background and Purpose- Cortical cerebral microinfarcts (CMIs) have been associated with vascular dementia and Alzheimer disease. The aim of the present study was to evaluate the role of cortical CMI detected on 3T magnetic resonance imaging, on the evolution of cognition during the year following an acute ischemic stroke. Methods- We conducted a prospective and monocentric study, including patients diagnosed for a supratentorial ischemic stroke with a National Institutes of Health Stroke Scale score ≥1, without prestroke dementia or neurological disability. Cortical CMIs were assessed on a brain 3T magnetic resonance imaging realized at baseline, as well as markers of small vessel disease, stroke characteristics, and hippocampal atrophy. Cognitive assessment was performed at 3 time points (baseline, 3 months, and 1 year) using the Montreal Cognitive Assessment, the Isaacs set test, and the Zazzo's cancellation task. Generalized linear mixed models were performed to evaluate the relationships between the number of cortical CMI and changes in cognitive scores over 1 year. Results- Among 199 patients (65±13 years old, 68% men), 88 (44%) had at least one cortical CMI. Hypertension was the main predictor of a higher cortical CMI load (B=0.58, P=0.005). The number of cortical CMI was associated with an increase time at the Zazzo's cancellation task over 1 year (B=3.84, P=0.01), regardless of the other magnetic resonance imaging markers, stroke severity, and demographic factors. Conclusions- Cortical CMIs are additional magnetic resonance imaging markers of poorer processing speed after ischemic stroke. These results indicate that a high load of cortical CMI in patients with stroke can be considered as a cerebral frailty condition which counteracts to the recovery process, suggesting a reduced brain plasticity among these patients.

The Influence of Stroke Location on Cognitive and Mood Impairment. A Voxel-Based Lesion-Symptom Mapping Study.

BACKGROUND AND PURPOSE: The role of stroke location as a determinant of mood and cognitive symptoms is still a matter of debate. The aim of this study was to identify the predictive value of ischemic stroke location, on a voxel basis, for mood and cognitive outcome. MATERIALS AND METHODS: A prospective monocentric study including patients with a supratentorial ischemic stroke was conducted. A 3 Tesla brain MRI was performed at baseline. Mood and cognition were assessed using Hospital Anxiety and Depression scale (HAD), apathy inventory (AI), and Montreal Cognitive Assessment scale subscores, performed at 3 months poststroke. Statistical maps of ischemic stroke location associated with 3 months mood and cognitive scores were obtained using a voxel-based lesion-symptom mapping approach (Brunner and Munzel test). Significant voxels (false discovery rate [FDR] corrected-P < .01) were identified using the standard Montreal Neurological Institute-152 space template. RESULTS: Two hundred and sixty-five nonsevere stroke patients were included (64% men, mean age 66 ± 14, median National Institute of Health Stroke Score 3, interquartile range 2-6). Ischemic stroke location was not associated with HAD or AI scores. Language, abstraction, and delayed recall performances were mainly associated with left-side hemispheric lesions. Lesions in both hemispheres were associated with lower performances in visuospatial and executive functions, naming, attention, and orientation. CONCLUSION: Ischemic stroke location does not predict mood outcome at 3 months but is a determinant of cognitive outcome in specific domains.

Thalamic alterations remote to infarct appear as focal iron accumulation and impact clinical outcome.

See Duering and Schmidt (doi:10.1093/awx135) for a scientific commentary on this article.Thalamic alterations have been observed in infarcts initially sparing the thalamus but interrupting thalamo-cortical or cortico-thalamic projections. We aimed at extending this knowledge by demonstrating with in vivo imaging sensitive to iron accumulation, one marker of neurodegeneration, that (i) secondary thalamic alterations are focally located in specific thalamic nuclei depending on the initial infarct location; and (ii) such secondary alterations can contribute independently to the long-term outcome. To tackle this issue, 172 patients with an infarct initially sparing the thalamus were prospectively evaluated clinically and with magnetic resonance imaging to quantify iron through R2* map at 24-72 h and at 1-year follow-up. An asymmetry index was used to compare R2* within the thalamus ipsilateral versus contralateral to infarct and we focused on the 95th percentile of R2* as a metric of high iron content. Spatial distribution within the thalamus was analysed on an average R2* map from the entire cohort. The asymmetry index of the 95th percentile within individual nuclei (medio-dorsal, pulvinar, lateral group) were compared according to the initial infarct location in simple and multiple regression analyses and using voxel-based lesion-symptom mapping. Associations between the asymmetry index of the 95th percentile and functional, cognitive and emotional outcome were calculated in multiple regression models. We showed that R2* was not modified at 24-72 h but showed heterogeneous increase at 1 year mainly within the medio-dorsal and pulvinar nuclei. The asymmetry index of the 95th percentile within the medio-dorsal nucleus was significantly associated with infarcts involving anterior areas (frontal P = 0.05, temporal P = 0.02, lenticular P = 0.01) while the asymmetry index of the 95th percentile within the pulvinar nucleus was significantly associated with infarcts involving posterior areas (parietal P = 0.046, temporal P < 0.001) independently of age, gender and infarct volume, which was confirmed by voxel-based lesion-symptom mapping. The asymmetry index of the 95th percentile within the entire thalamus at 1 year was independently associated with poor functional outcome (P = 0.04), poor cognitive outcome (P = 0.03), post-stroke anxiety (P = 0.04) and post-stroke depression (P = 0.02). We have therefore identified that iron accumulates within the thalamus ipsilateral to infarct after a delay with a focal distribution that is strongly linked to the initial infarct location (in relation with the pattern of connectivity between thalamic nuclei and cortical areas or deep nuclei), which independently contributes to functional, cognitive and emotional outcome.

Admission Brain Cortical Volume: An Independent Determinant of Poststroke Cognitive Vulnerability.

BACKGROUND AND PURPOSE: Several markers of poststroke cognitive impairment have been reported. The role of brain cortical volume remains uncertain. The aim of this study was to evaluate the influence of brain cortical volume on cognitive outcomes using a voxel-based morphometry approach in subjects without prestroke dementia. METHODS: Ischemic stroke patients were prospectively recruited 24 to 72 hours post stroke (M0). Cognition was evaluated at M0, 3 months, and 1 year (M12) using the Montreal Cognitive Assessment, the Isaacs set test, and the Zazzo's cancellation task. A 3-T brain magnetic resonance imaging was performed at M0. Grey matter (GM) was segmented using Statistical Parametric Mapping 12 software. Association between global GM volume and cognitive score slopes between M0 and M12 was evaluated using a linear mixed model. Correlations between focal GM volumes and changes in cognitive performance were evaluated using Statistical Parametric Mapping 12. RESULTS: Two-hundred forty-eight patients were included (mean age 65±SD 14 years old, 66% men). Global GM volume was significantly associated with changes in Montreal Cognitive Assessment scores (ß=0.01; P=0.04) and in the number of errors on the Zazzo's cancellation task (ß=-0.02; P=0.04) independently of other clinical/radiological confounders. Subjects with lower GM volumes in the left fronto-temporo-insular cortex were more vulnerable to transient Montreal Cognitive Assessment and Isaacs set test impairment. Subjects with lower GM volumes in right temporo-insular cortex, together with basal ganglia, were more vulnerable to transient cognitive impairment on the Zazzo's cancellation task. CONCLUSIONS: Smaller cortical volumes in fronto-temporo-insular areas measured 24 to 72 hours post stroke are associated with cognitive vulnerability in the subacute stroke phase.

Early Fiber Number Ratio Is a Surrogate of Corticospinal Tract Integrity and Predicts Motor Recovery After Stroke.

BACKGROUND AND PURPOSE: The contribution of imaging metrics to predict poststroke motor recovery needs to be clarified. We tested the added value of early diffusion tensor imaging (DTI) of the corticospinal tract toward predicting long-term motor recovery. METHODS: One hundred seventeen patients were prospectively assessed at 24 to 72 hours and 1 year after ischemic stroke with diffusion tensor imaging and motor scores (Fugl-Meyer). The initial fiber number ratio (iFNr) and final fiber number ratio were computed as the number of streamlines along the affected corticospinal tract normalized to the unaffected side and were compared with each other. The prediction of motor recovery (ΔFugl-Meyer) was first modeled using initial Fugl-Meyer and iFNr. Multivariate ordinal logistic regression models were also used to study the association of iFNr, initial Fugl-Meyer, age, and stroke volume with Fugl-Meyer at 1 year. RESULTS: The iFNr correlated with the final fiber number ratio at 1 year (r=0.70; P<0.0001). The initial Fugl-Meyer strongly predicted motor recovery (≈73% of initial impairment) for all patients except those with initial severe stroke (Fugl-Meyer<50). For these severe patients (n=26), initial Fugl-Meyer was not correlated with motor recovery (R(2)=0.13; p=ns), whereas iFNr showed strong correlation (R(2)=0.56; P<0.0001). In multivariate analysis, the iFNr was an independent predictor of motor outcome (ß=2.601; 95% confidence interval=0.304-5.110; P=0.031), improving prediction compared with using only initial Fugl-Meyer, age, and stroke volume (P=0.026). CONCLUSIONS: Early measurement of FNr at 24 to 72 hours poststroke is a surrogate marker of corticospinal tract integrity and provides independent prediction of motor outcome at 1 year especially for patients with severe initial impairment.

Stroke Location Is an Independent Predictor of Cognitive Outcome.

BACKGROUND AND PURPOSE: On top of functional outcome, accurate prediction of cognitive outcome for stroke patients is an unmet need with major implications for clinical management. We investigated whether stroke location may contribute independent prognostic value to multifactorial predictive models of functional and cognitive outcomes. METHODS: Four hundred twenty-eight consecutive patients with ischemic stroke were prospectively assessed with magnetic resonance imaging at 24 to 72 hours and at 3 months for functional outcome using the modified Rankin Scale and cognitive outcome using the Montreal Cognitive Assessment (MoCA). Statistical maps of functional and cognitive eloquent regions were derived from the first 215 patients (development sample) using voxel-based lesion-symptom mapping. We used multivariate logistic regression models to study the influence of stroke location (number of eloquent voxels from voxel-based lesion-symptom mapping maps), age, initial National Institutes of Health Stroke Scale and stroke volume on modified Rankin Scale and MoCA. The second part of our cohort was used as an independent replication sample. RESULTS: In univariate analyses, stroke location, age, initial National Institutes of Health Stroke Scale, and stroke volume were all predictive of poor modified Rankin Scale and MoCA. In multivariable analyses, stroke location remained the strongest independent predictor of MoCA and significantly improved the prediction compared with using only age, initial National Institutes of Health Stroke Scale, and stroke volume (area under the curve increased from 0.697-0.771; difference=0.073; 95% confidence interval, 0.008-0.155). In contrast, stroke location did not persist as independent predictor of modified Rankin Scale that was mainly driven by initial National Institutes of Health Stroke Scale (area under the curve going from 0.840 to 0.835). Similar results were obtained in the replication sample. CONCLUSIONS: Stroke location is an independent predictor of cognitive outcome (MoCA) at 3 months post stroke.

Microstructural Gray Matter Integrity Deteriorates After an Ischemic Stroke and Is Associated with Processing Speed.

Microstructural changes after an ischemic stroke (IS) have mainly been described in white matter. Data evaluating microstructural changes in gray matter (GM) remain scarce. The aim of the present study was to evaluate the integrity of GM on longitudinal data using mean diffusivity (MD), and its influence on post-IS cognitive performances. A prospective study was conducted, including supra-tentorial IS patients without pre-stroke disability. A cognitive assessment was performed at baseline and 1 year, including a Montreal Cognitive Assessment, an Isaacs set test, and a Zazzo cancelation task (ZCT): completion time and number of errors. A 3-T brain MRI was performed at the same two time-points, including diffusion tensor imaging for the assessment of GM MD. GM volume was also computed, and changes in GM volume and GM MD were evaluated, followed by the assessment of the relationship between these structural changes and changes in cognitive performances. One hundred and four patients were included (age 68.5 ± 21.5, 38.5% female). While no GM volume loss was observed, GM MD increased between baseline and 1 year. The increase of GM MD in left fronto-temporal regions (dorsolateral prefrontal cortex, superior and medial temporal gyrus, p < 0.05, Threshold-Free Cluster Enhancement, 5000 permutations) was associated with an increase time to complete ZCT, regardless of demographic confounders, IS volume and location, GM, and white matter hyperintensity volume. GM integrity deterioration was thus associated with processing speed slowdown, and appears to be a biomarker of cognitive frailty. This broadens the knowledge of post-IS cognitive impairment mechanisms.

Normal-Appearing White Matter Deteriorates over the Year After an Ischemic Stroke and Is Associated with Global Cognition.

Normal-appearing white matter (NAWM) is a hub of plasticity, but data relating to its influence on post-ischemic stroke (IS) outcome remain scarce. The aim of this study was to evaluate the relationship between NAWM integrity and cognitive outcome after an IS. A longitudinal study was conducted including supra-tentorial IS patients. A 3-Tesla brain MRI was performed at baseline and 1 year, allowing the analyses of mean fractional anisotropy (FA) and mean diffusivity (MD) in NAWM masks, along with the volume of white matter hyperintensities (WMH) and IS. A Montreal Cognitive Assessment (MoCA), an Isaacs set test, and a Zazzo's cancellation task were performed at baseline, 3 months and 1 year. Mixed models were built, followed by Tract-based Spatial Statistics (TBSS) analyses. Ninety-five patients were included in the analyses (38% women, median age 69 ± 20). FA significantly decreased, and MD significantly increased between baseline and 1 year, while cognitive scores improved. Patients who decreased their NAWM FA more over the year had a slower cognitive improvement on MoCA (ß = - 0.11, p = 0.05). The TBSS analyses showed that patients who presented the highest decrease of FA in various tracts of white matter less improved their MoCA performances, regardless of WMH and IS volumes, demographic confounders, and clinical severity. NAWM integrity deteriorates over the year after an IS, and is associated with a cognitive recovery slowdown. The diffusion changes recorded here in patients starting with an early preserved white matter structure could have long term impact on cognition.

Major intra-familial phenotypic heterogeneity and incomplete penetrance due to a CACNA1A pathogenic variant.

The CACNA1A gene encodes a calcium-dependent voltage channel, localized in neuronal cells. Pathogenic variants in this gene are known to lead to a broad clinical spectrum including episodic ataxia type 2, spinocerebellar ataxia type 6, familial hemiplegic migraine, and more recently epileptic encephalopathy. We report a large family revealing a wide variability of neurological manifestations associated with a CACNA1A missense pathogenic variant. The index case had early-onset epileptic encephalopathy with progressive cerebellar atrophy, although his mother and his great-grandmother suffered from paroxystic episodic ataxia. His grandfather and great grand-aunt reported no symptoms, but two of her sons displayed early-onset ataxia with intellectual disability. Two of her little daughters suffered from gait disorders, and also from epilepsy for one of them. All these relatives were carriers of the previously described heterozygous variant in CACNA1A gene. We report here the first family leading to major clinical variability and incomplete penetrance. Our family highlights the difficulties to provide accurate genetic counselling concerning prenatal diagnosis regarding highly variable severity of the clinical presentation.