Tract‐specific analysis and neurocognitive functioning in sickle cell patients without history of overt stroke

International audienceSickle cell disease (SCD) is a hereditary blood disorder in which the oxygen‐carrying hemoglobin molecule in red blood cells is abnormal. SCD patients are at increased risks for strokes and neurocognitive deficit, even though neurovascular screening and treatments have lowered the rate of overt strokes. Tract‐specific analysis (TSA) is a statistical method to evaluate microstructural WM damage in neurodegenerative disorders, using diffusion tensor imaging (DTI). We utilized TSA and compared 11 major brain WM tracts between SCD patients with no history of overt stroke, anemic controls, and healthy controls. We additionally examined the relationship between the most commonly used DTI metric of WM tracts and neurocognitive performance in the SCD patients and healthy controls. Disruption of WM microstructure orientation‐dependent metrics for the SCD patients was found in the genu of the corpus callosum (CC), cortico‐spinal tract, inferior fronto‐occipital fasciculus, right inferior longitudinal fasciculus, superior longitudinal fasciculus, and left uncinate fasciculus. Neurocognitive performance indicated slower processing speed and lower response inhibition skills in SCD patients compared to controls. TSA abnormalities in the CC were significantly associated with measures of processing speed, working memory, and executive functions. Decreased DTI‐derived metrics were observed on six tracts in chronically anemic patients, regardless of anemia subtype, while two tracks with decreased measures were unique to SCD patients. Patients with WMHs had more significant FA abnormalities. Decreased FA values in the CC significantly correlated with all nine neurocognitive tests, suggesting a critical importance for CC in core neurocognitive processes

Correlation results between regional mean ALFF and neurocognitive scores.

<p>Correlation results between regional mean ALFF and neurocognitive scores.</p

Statistic results between the SCD patients with and without WMHs.

<p>Statistic results between the SCD patients with and without WMHs.</p

Representative one-sample <i>t</i>-test result of ALFF maps.

<p>(A) CTL subjects. (B) ACTL subjects. (C) SCD subjects. Color scale indicates t-values, resulting from one one sample t-test. Thresholds were set at a AlphaSim corrected p<0.05, determined by Monte Carlo simulation. In the Montreal Neurological Institute (MNI) template, the planes are X = -4mm, Z = -32mm and Y = -52mm for the sagittal, axial and coronal views, respectively.</p

Demographic and clinical variables among healthy controls (CTL), anemic control subjects (ACTL) and patients with sickle cell disease (SCD) including the transfused (NTx) and the non-transfused patients.

<p>Demographic and clinical variables among healthy controls (CTL), anemic control subjects (ACTL) and patients with sickle cell disease (SCD) including the transfused (NTx) and the non-transfused patients.</p

Cerebral volumes (expressed as mean ± standard deviation) of healthy controls (CTL), anemic control subjects (ACTL) and patients with sickle cell disease (SCD) and the p-values of SCD vs. CTL.

<p>Cerebral volumes (expressed as mean ± standard deviation) of healthy controls (CTL), anemic control subjects (ACTL) and patients with sickle cell disease (SCD) and the p-values of SCD vs. CTL.</p

Differences in ALFF values between ACTL, SCD and CTL groups.

<p>All thresholds were set at a AlphaSim corrected p<0.05. Color scale indicates t-values, resulting from two sample t-test. Numbers and arrows represent anatomical location. Numbers and arrows represent anatomical location. A. Representative two-sample <i>t</i>-test results of ALFF maps between the ACTL versus CTL groups showing the right mSFG (arrow 1) and left insula (arrow 2). B. Representative two-sample <i>t</i>-test results of ALFF maps between the SCD versus CTL groups. Seven clusters are indicated by arrows: OFC (arrow 3), right paracentral lobule (arrow 4), PCC (arrow 5), cerebellum (arrow 6), frontal pole (arrow 7), left precuneus (arrow 8) and left insula (arrow 2). C. Representative two-sample <i>t</i>-test results of ALFF maps between the SCD versus ACTL groups. Compared with values in the ACTL group, ALFF in SCD patients increased in OFC (3) and decreased in right mSFG (arrow 1), cerebellum (arrow 6) and frontal pole (arrow 7).</p

Venn diagram representing changes (from normal) seen in SCD and ACTL groups.

<p>The changes are grouped with regards to their cause. They could be either unique to SCD patients (left/grey), common to SCD and ACTL patients (middle) or unique to ACTL patients (right/blue). OFC: orbital frontal cortex; ACC: anterior cingulate cortex; PCC: posterior cingulate cortex; mSFG: medial superior frontal gyrus.</p

Contrasting resting-state fMRI abnormalities from sickle and non-sickle anemia

Sickle cell disease (SCD) is a chronic blood disorder that is often associated with acute and chronic cerebrovascular complications, including strokes and impaired cognition. Using functional resting state magnetic resonance images, we performed whole-brain analysis of the amplitude of low frequency fluctuations (ALFF), to detect areas of spontaneous blood oxygenation level dependent signal across brain regions. We compared the ALFF of 20 SCD patients to that observed in 19 healthy, age and ethnicity-matched, control subjects. Significant differences were found in several brain regions, including the insula, precuneus, anterior cingulate cortex and medial superior frontal gyrus. To identify the ALFF differences resulting from anemia alone, we also compared the ALFF of SCD patients to that observed in 12 patients having comparable hemoglobin levels but lacking sickle hemoglobin. Increased ALFF in the orbitofrontal cortex and the anterior and posterior cingulate cortex and decreased ALFF in the frontal pole, cerebellum and medial superior frontal gyrus persisted after accounting for the effect of anemia. The presence of white matter hyperintensities was associated with depressed frontal and medial superior frontal gyri activity in the SCD subjects. Decreased ALFF in the frontal lobe was correlated with decreased verbal fluency and cognitive flexibility. These findings may lead to a better understanding of the pathophysiology of SCD