Frontal White Matter Research Articles

A link between frontal white matter integrity and dizziness in cerebral small vessel disease

One in three older people (>60 years) complain of dizziness which often remains unexplained despite specialist assessment. We investigated if dizziness was associated with vascular injury to white matter tracts relevant to balance or vestibular self-motion perception in sporadic cerebral small vessel disease (age-related microangiopathy). We prospectively recruited 38 vestibular clinic patients with idiopathic (unexplained) dizziness and 36 age-matched asymptomatic controls who underwent clinical, cognitive, balance, gait and vestibular assessments, and structural and diffusion brain MRI. Patients had more vascular risk factors, worse balance, worse executive cognitive function, and worse ankle vibration thresholds in association with greater white matter hyperintensity in frontal deep white matter, and lower fractional anisotropy in the genu of the corpus callosum and the right inferior longitudinal fasciculus. A large bihemispheric white matter network had less structural connectivity in patients. Reflex and perceptual vestibular function was similar in patients and controls. Our results suggest cerebral small vessel disease is involved in the genesis of dizziness through its effect on balance.

Predictors and integrative index of severity of cognitive disorders in cerebral microangiopathy

To search for sensitive predictors of cognitive impairment (CI) and an integrative index of their severity. We assessed CI and diffusion-tensor MRI (DT-MRI) in the regions of interest (ROI) significant for CI in 74 patients (48 women, mean age 60.6±6.9 years) with cerebral small vessel disease (CSVD). The results of DT-MRI were used to construct a predictive model of CI using binary logistic regression and to calculate an integrative index of CI severity. According to the constructed model, the predictors of CI were axial diffusivity (AD) of posterior frontal periventricular normal-appearing white matter (pvNAWM), right middle cingulum bundle (CB) and mid-posterior corpus callosum (CC). ROC analysis showed strong model predictive power for CI in cSVD (AUC (95% CI): 0.845 (0.740-0.950)). The threshold value of the AD predictors model for CI in cSVD was 0.53 (sensitivity 84%, specificity 76%). AD predictors of CI showed significant correlations with white matter hyperintensities volume and MoCA scores. The presence of CI as measured by neuropsychological testing and regression equation solution was corresponded to individual AD predictors of patients exceeding the CI model's threshold. Disturbances in the AD of pvNAWM, right middle CB and mid-posterior CC associated with axonal damage are a predominant factor in the development of CI in CSVD. The predictors of CI and the integrative index of CI severity calculated on their basis can potentially be used as a tool for assessing the severity of CI and the effectiveness of treatment, as well as in clarifying the interaction between vascular and degenerative pathology and in developing measures for the prevention of CI in patients with MRI signs of cSVD.

Subacute Sclerosing Panencephalitis: Restricted Diffusion and Clinical Evolution.

Subacute sclerosing panencephalitis (SSPE) is a rare entity characterized by a protracted course and progressive neurological deterioration. We present patterns of diffusion restriction in eight cases of SSPE, a seldom described imaging attribute. A retrospective analysis was performed on the clinical and neuroimaging data obtained from records of patients with proven SSPE. Patients whose magnetic resonance imaging (MRI) showed evidence of diffusion restriction were included in the analysis. MRI was performed on 3 T and 1.5-T clinical MR systems. Imaging characteristics were reviewed and tabulated by two neuroradiologists. Eight SSPE patients (seven men, one woman; age range: 5-15 years; mean age: 11 years) diagnosed and managed at our institute were included in the analysis. Restricted diffusion was evident in the basal ganglia (n = 3), corpus callosum (n = 2), white matter (n = 2) and in bilateral middle cerebellar peduncles (MCP) (n = 2). One patient had diffusion restriction in the genu of the corpus callosum and bilateral frontal cortical white matter. None of the diffusion-restricted lesions showed contrast enhancement or susceptibility. Six cases fulfilled the diagnostic criteria for fulminant SSPE (fSSPE). The extent of neuroparenchymal involvement was greater in this subset of patients. Restricted diffusion in SSPE, hitherto infrequently described, can indeed occur in both grey and white matter structures and in both supratentorial and infratentorial compartments. Parenchymal diffusion restriction in SSPE possibly reflects an early time point in the clinical evolution. A greater extent of parenchymal diffusion restriction may portend a rapid downhill course, possibly qualifying for fSSPE.

Diagnostic performance of arterial spin-labeled perfusion imaging and diffusion-weighted imaging in full-term neonatal hypoxic-ischemic encephalopathy.

We evaluated the performance of arterial spin-labeled perfusion imaging and diffusion-weighted imaging in diagnosing full-term neonatal hypoxic-ischemic encephalopathy. Arterial spin-labeled, diffusion-weighted imaging and conventional magnetic resonance imaging (T1-weighted imaging, T2-weighted imaging and T2 fluid-attenuated inversion recovery) were performed in 23 full-term neonates with hypoxic-ischemic encephalopathy group 10 normal neonates (Control group). The cerebral blood flow and the apparent diffusion coefficient were measured in the bilateral basal ganglia, thalamus and frontal white matter. The effect of neonatal age on the CBF and apparent diffusion coefficient values were further investigated after dividing the 23 ischemic encephalopathy cases into three subgroups (1-3 days, 4-7 days, and 8-15 days). The cerebral blood flow values in the thalamus and lenticular nucleus were significantly higher. The apparent diffusion coefficient values in the thalamus, frontal white matter and lenticular nucleus head were significantly lower in the hypoxic-ischemic encephalopathy group than those in the Control group (p < 0.05). There were no significant differences between the ischemic encephalopathy and Control groups in the cerebral blood flow values in the caudate nucleus head and frontal lobe white matter (p > 0.05). The cerebral blood flow and apparent diffusion coefficient values in the thalamus and lenticular nucleus were negatively correlated. Comparison among different age subgroups of hypoxic-ischemic encephalopathyneonates showed that the cerebral blood flow value was higher. In comparison, the apparent diffusion coefficient value was lower in the 1-3 days old neonates than those in the older neonates (p < 0.05). Arterial spin-labeled and diffusion-weighted imaging could reflect the ischemic encephalopathy pathological processes more comprehensively. The cerebral blood flow measurement and apparent diffusion coefficient values in the thalamus and the lenticular nucleus may represent a novel way to diagnose ischemic encephalopathy early.

Quantitative Diffusion and Spectroscopic Neuroimaging Combined with a Novel Early-Developmental Assessment Improves Models for 1-Year Developmental Outcomes.

Preterm infants are at risk for overt and silent CNS injury, with developmental consequences that are difficult to predict. The novel Specific Test of Early Infant Motor Performance, administered in preterm infants at term age, is indicative of later developmental gross motor and cognitive scores at 12 months. Here, we assessed whether functional performance on this early assessment correlates with CNS integrity via MR spectroscopy or diffusional kurtosis imaging and whether these quantitative neuroimaging methods improve predictions for future 12-month developmental scores. MR spectroscopy and quantitative diffusion MR imaging data were acquired in preterm infants (n = 16) at term. Testing was performed at term and 3 months using the Specific Test of Early Infant Motor Performance and the Bayley Scales of Infant and Toddler Development, Third Edition, at 12 months. We modeled the relationship of MR spectroscopy and diffusion MR imaging data with both test scores via multiple linear regression. MR spectroscopy NAA ratios at a TE of 270 ms in the frontal WM and basal ganglia and kurtosis metrics in major WM tracts correlated strongly with total Specific Test of Early Infant Motor Performance scores. The addition of MR spectroscopy and diffusion separately improved the functional predictions of 12-month outcomes. Microstructural integrity of the major WM tracts and metabolism in the basal ganglia and frontal WM strongly correlate with early developmental performance, suggesting that the Specific Test of Early Infant Motor Performance reflects CNS integrity after preterm birth. This study demonstrates that combining quantitative neuroimaging and early functional movement improves the prediction of 12-month outcomes in premature infants.

Age, Sex, and Cerebral Microbleeds Affect White Matter Integrity Across Adulthood After Mild Traumatic Brain Injury

The contributions of age, sex, and cerebral microbleeds (CMBs) to WM changes after mild traumatic brain injury (mTBI) have not been studied. We used diffusion tensor imaging (DTI) to map WM fractional anisotropy (FA) changes across the first ~6 months post-mTBI in 109 subjects aged 18-77 (46 females; age µ: 40 y, σ: 17 y) imaged within ~1 week post-injury and ~6 months later. After partialing out age, sex, and CMB counts, significant mean FA decreases were found in the anterior body, posterior body, and splenium of the corpus callosum (CC; p = 0.003, 0.009 and 0.015, respectively), left superficial frontal fasciculus (p = 0.008), and left branch of the corticospinal tract (CST; p = 0.007). Age contributed to mean FAs measured acutely in the CC body (p = 0.04), and chronically in the CC genu (p < 0.001), CC body (p = 0.01), and middle longitudinal fasciculi (p = 0.04), older adults exhibiting larger decreases. CMB counts were positively associated with mean FA decreases in the CC body (p = 0.04) and middle longitudinal fasciculi (p = 0.04). Significant age-by-sex and CMB count-by-age interactions mediated FA decreases in the CC genu (p = 0.02 and p = 0.03, respectively), older males exhibiting larger decreases. Thus, the CC, longitudinal fasciculi, superficial frontal WM and CST are particularly vulnerable to post-traumatic neurodegeneration moderated by age, sex and CMB count, men and older adults being at highest risk for adverse effects. Future research should investigate our findings relative to cognitive function.

Distinct patterns of progressive gray and white matter degeneration in amyotrophic lateral sclerosis.

Progressive cerebral degeneration in amyotrophic lateral sclerosis (ALS) remains poorly understood. Here, three‐dimensional (3D) texture analysis was used to study longitudinal gray and white matter cerebral degeneration in ALS from routine T1‐weighted magnetic resonance imaging (MRI). Participants were included from the Canadian ALS Neuroimaging Consortium (CALSNIC) who underwent up to three clinical assessments and MRI at four‐month intervals, up to 8 months after baseline (T 0). Three‐dimensional maps of the texture feature autocorrelation were computed from T1‐weighted images. One hundred and nineteen controls and 137 ALS patients were included, with 81 controls and 84 ALS patients returning for at least one follow‐up. At baseline, texture changes in ALS patients were detected in the motor cortex, corticospinal tract, insular cortex, and bilateral frontal and temporal white matter compared to controls. Longitudinal comparison of texture maps between T 0 and T max (last follow‐up visit) within ALS patients showed progressive texture alterations in the temporal white matter, insula, and internal capsule. Additionally, when compared to controls, ALS patients had greater texture changes in the frontal and temporal structures at T max than at T 0. In subgroup analysis, slow progressing ALS patients had greater progressive texture change in the internal capsule than the fast progressing patients. Contrastingly, fast progressing patients had greater progressive texture changes in the precentral gyrus. These findings suggest that the characteristic longitudinal gray matter pathology in ALS is the progressive involvement of frontotemporal regions rather than a worsening pathology within the motor cortex, and that phenotypic variability is associated with distinct progressive spatial pathology.

The Value of Diffusion Kurtosis Imaging in Detecting Delayed Brain Development of Premature Infants.

Objective: Preterm infants are at high risk of the adverse neurodevelopmental outcomes. Our aim is to explore the value of diffusion kurtosis imaging (DKI) in diagnosing brain developmental disorders in premature infants.Materials and Methods: A total of 52 subjects were included in this study, including 26 premature infants as the preterm group, and 26 full-term infants as the control group. Routine MRI and DKI examinations were performed. Mean kurtosis (MK), radial kurtosis (RK), fractional anisotropy (FA), and mean diffusivity (MD) values were measured in the brain regions including posterior limbs of the internal capsule (PLIC), anterior limb of internal capsule (ALIC), parietal white matter (PWM), frontal white matter (FWM), thalamus (TH), caudate nucleus (CN), and genu of the corpus callosum (GCC). The chi-squared test, t-test, Spearman's correlation analysis, and receiver operating characteristic curve were used for data analyses.Results: In the premature infant group, the MK and RK values of PLIA, ALIC, and PWM were lower than those in the control group (p < 0.05). The FA values of PWM, FWM, and TH were also lower than those of the control group (p < 0.05). The area under curves of MK in PLIC and ALIC, MD in PWM, and FA in FWM were 0.813, 0.802, 0.842, and 0.867 (p < 0.05). In the thalamus and CN, the correlations between MK, RK values, and postmenstrual age (PMA) were higher than those between FA, MD values, and PMA.Conclusion: Diffusion kurtosis imaging can be used as an effective tool in detecting brain developmental disorders in premature infants.

Spatial pattern of R 2 relaxation rate is associated with limbic‐predominant, age‐related, TDP‐43 encephalopathy neuropathological change (LATE‐NC)

Limbic predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) refers to the stereotypical accumulation of TDP-43 proteinopathy in older adults, and has been associated with lower memory, cognitive decline and increased likelihood of dementia. However, association of R2 with LATE-NC is still unclear. In this work, we examined the association and spatial profile of R2 alterations with LATE-NC in a large community cohort of older adults. This study included 797 individuals participating in three longitudinal studies: Rush Memory and Aging Project, Religious Orders Study, and Minority Aging Research Study (Fig. 1). Ex-vivo images were collected using a 2D multi-echo spin-echo (ME-SE) sequence. Afterwards, detailed neuropathologic examination was performed by a board-certified neuropathologist blinded to all data (Fig. 2). The R2 relaxation rate was quantified voxel-wise by fitting a monoexponential decay function S = S0 ∙exp(-R2 ∙t) to the ME-SE data. Images from one of the echoes were non-linearly registered to a brain template, and the resulting transformations were applied to the R2 -maps to enable voxel-wise analysis. Voxel-wise linear regression was used to investigate the association of R2 relaxation rate with LATE-NC controlling for Alzheimer's pathology, Lewy bodies, gross and microscopic infarcts, atherosclerosis, cerebral amyloid angiopathy, arteriolosclerosis, as well as age at death, sex, years of education, postmortem interval to fixation and postmortem interval to imaging, and scanner. Statistical significance was set at p<0.05. Voxel-wise analysis demonstrated lower R2 for greater LATE-NC burden in a number of brain regions in the temporal, frontal, occipital lobes and basal ganglia (Fig. 3). The strongest effects were observed in the amygdala, hippocampus, and neighboring temporal lobe regions. In addition, lower R2 with greater LATE-NC burden was demonstrated in the caudate, insular, frontal and occipital white matter regions. No brain regions showed positive associations of R2 with LATE-NC. The present study demonstrated a spatial pattern of lower R2 relaxation rate for greater LATE-NC burden in a large community cohort of older adults. This pattern involved mainly the temporal, frontal, occipital lobes and basal ganglia. The link between R2 and LATE-NC may be exploited towards the development of algorithms for the prediction of this devastating, recently recognized disease entity.

Imaging measures of molecular pathology and neurodegeneration in dominantly‐inherited and sporadic early‐onset Alzheimer’s Disease

AbstractBackgroundApproximately 5% of patients with Alzheimer’s Disease (AD) develop symptoms before age 65, with this early‐onset presentation attributed to either sporadic (sEOAD) or dominantly‐inherited (DIAD) etiology. Both sEOAD and DIAD are characterized by brain amyloid‐beta (Aβ) accumulation and neurodegeneration, but differences in topography and magnitude of these pathological changes are not fully elucidated.MethodWe included 108 sEOAD Aβ‐PET positive cases from the UCSF Alzheimer’s Disease Research Center (mean±standard deviation age 59.7±5.4 years) and 86 DIAD cases from the Dominantly Inherited Alzheimer Network (DIAN) study (age 45.5±9.5 years) with symptom onset before 65 years (see Table 1). All cases were symptomatic (clinical dementia rating [CDR] global ≥0.5) and underwent standard clinical and cognitive measures, 11C‐PiB‐PET (Aβ), 18F‐FDG‐PET (glucose metabolism) and structural MRI. PET scans were processed to obtain Standardized Uptake Value Ratio (SUVR, PIB50‐70, FDG30‐60) images. Warped PET SUVR and modulated, warped gray matter images were compared across the two cohorts with SPM12 after smoothing to ∼8mm3, covarying for age, CDR sum of boxes, years of education, APOE e4 status, and respective global biomarker score. A‐priori statistical threshold was set at p&lt;0.001 uncorrected, with a Family Wise Error p&lt;0.05 correction at the cluster‐level.ResultsEOAD participants were older, more educated, had greater cognitive impairment, had higher Aβ burden and were more likely to be APOE ε4 carriers (see Table 1). sEOAD participants exhibited higher relative PIB‐PET binding in anterior temporal and frontal (mostly white matter) regions, as well as lower relative FDG‐PET binding and sMRI‐based volumes in temporoparietal regions. DIAD participants showed higher relative PIB‐PET binding in the medial occipital, thalami, basal ganglia (caudate nuclei and putamen) and medial/dorsal frontal regions. DIAD participants showed lower relative FDG‐PET binding mostly in the frontal and parietal white matter (see Figure 1).ConclusionAβ pathology in DIAD was more likely to affect subcortical systems, whereas both Aβ pathology and neurodegeneration tended to be relatively more cortical and extensive in sEOAD. These results highlight EOAD heterogeneity and show that sporadic and inherited AD exhibit distinct regional vulnerabilities in neurodegeneration as well as differing topography and magnitude of biomarker abnormalities.

Higher systolic and diastolic blood pressures are associated with loss of white matter integrity in postmenopausal women of the KEEPS Continuation Study

AbstractBackgroundElevated systolic blood pressure (SBP) and diastolic blood pressure (DBP) are risk factors for white matter (WM) injury associated with cognitive decline and dementia. White matter hyperintensities (WMH) on MRI, markers of WM injury, increase with aging and are more common in women than in men after the age of 60. We examined SBP and DBP in relation to WMH volume and diffusion MRI measures of WM integrity in postmenopausal women.MethodWomen (n=144) with median age of 67 (range 58‐72) and of good cardiovascular health who were previously enrolled in the multi‐site randomized clinical trial, Kronos Early Estrogen Prevention Study (KEEPS), participated in the present observational KEEPS Continuation Study. SBP, DBP, and MRI data were collected approximately 9 years after the end of KEEPS menopausal hormones versus placebo 4‐year interventions. WM integrity was assessed with WMH volume measurements (log transformed) on structural MRI and with measures of WM microstructure on diffusion MRI. Multiple linear regression analyses, adjusted for age, were used to test for associations of SBP and DBP with MRI measures.ResultThe median SBP was 128 (range 86‐180) and DBP was 77 (range 47‐106). Higher SBP (r=0.332;p=0.015) and DBP (r=0.346;p=0.007) were associated with higher WMH volumes. Among the WM tracts, higher SBP was associated with lower fractional anisotropy (FA) in lateral orbitofrontal gyrus WM (r=0.198;p=0.039) and sagittal stratum (r=0.226;p=0.043), and higher DBP was associated with lower FA in the superior occipital gyrus WM (r=0.370;p=0.045). Higher SBP and DBP were associated with higher mean diffusivity (MD) in the external capsule [(r=0.311;p=0.007);(r=375;p&lt;0.001)] and the fronto‐occipital fasciculus [(r=0.286;p=0.016); (r=0.303;p=0.008)]. Furthermore, higher DBP was associated with higher MD in the anterior corona radiata (r=0.233;p=0.039), internal capsule (r=0.303;p=0.042), and the middle (r=0.275; p=0.03) and superior frontal gyrus (r=0.269;p=0.03) WM.ConclusionElevated SBP and DBP measurements are associated with greater WM injury in postmenopausal women. In particular, the frontal lobe WM and its connecting tracts may be more vulnerable to elevation in SBP and DBP. Whether BP control reduces the risk for WM injury, a risk factor for dementia, in post‐menopausal women warrants study.

Neuroimaging‐derived phenotypes in the European Prevention of Alzheimer Dementia (EPAD) Cohort Study

AbstractBackgroundNeuroimaging biomarkers in large‐scale multimodal studies have proven effective for early diagnosis. Image‐derived phenotypes (IDPs) are summary features derived from modalities such as magnetic resonance imaging (MRI). We provide an overview of the IDPs computed from the European Prevention of Alzheimer Dementia (EPAD) cohort study, a multi‐center European study including multimodal brain MRI.MethodBaseline data from the first 1500 participants of the EPAD LCS were included. The imaging protocol consists of core (3D‐T1w, 3D‐FLAIR, 2D‐T2w, 2D‐T2*), and advanced (resting‐state fMRI, SWI, diffusion MRI, and ASL) sequences. 3D‐T1w IDPs consisted of regional volumes derived from FreeSurfer v6.0 and the Learn Embeddings for Atlas Propagation (LEAP) segmentation pipelines and 3D‐FLAIR IDPs were white matter hyperintensity (WMH) volumes measured by Bayesian Model Selection (BaMoS). Mean functional connectivity of rs‐fMRI networks was extracted with FSL MELODIC and dual‐regression analyses. For diffusion‐weighted imaging, we used FSL TBSS to quantify 48 regional fractional anisotropy (FA) values according to the JHU atlas of white matter tracts. ExploreASL was used to calculate mean Cerebral blood flow (CBF) and spatial coefficient‐of‐variation (sCoV) from ASL images. To evaluate the biological relevance of IDPs, we assessed their relationship with non‐imaging phenotypes.ResultA total of 358 core and 119 advanced IDPs were derived. GM volume was inversely correlated with age, with stronger effects in medio‐temporal areas (Figure 1). Regional WMH volumetrics showed mostly frontal and parietal WM lesions that were associated with aging (Figure 2). Heterogeneous changes in within‐network functional connectivity were observed with older age, with mild differences between CDR 0 and 0.5 contrasts, mostly related to the default‐mode and frontoparietal networks (Figure 3). Age was also associated inversely with skeletonised FA values. Stronger reductions appeared in amyloid positive participants (Figure 4).ConclusionWe show the relevance of IDPs from the EPAD neuroimaging dataset. The observed relationships with non‐imaging phenotypes confirm their biological relevance and are in agreement with previous studies. The proposed IDP framework may constitute a valuable resource for researchers using EPAD data, promoting reproducibility of results and easily adaptable for other studies and cohorts.

Expanded phenotype of AARS1-related white matter disease

Recent reports of individuals with cytoplasmic transfer RNA (tRNA) synthetase-related disorders have identified cases with phenotypic variability from the index presentations. We sought to assess phenotypic variability in individuals with AARS1-related disease. A cross-sectional survey was performed on individuals with biallelic variants in AARS1. Clinical data, neuroimaging, and genetic testing results were reviewed. Alanyl tRNA synthetase (AlaRS) activity was measured in available fibroblasts. We identified 11 affected individuals. Two phenotypic presentations emerged, one with early infantile-onset disease resembling the index cases of AARS1-related epileptic encephalopathy with deficient myelination (n = 7). The second (n = 4) was a later-onset disorder, where disease onset occurred after the first year of life and was characterized on neuroimaging by a progressive posterior predominant leukoencephalopathy evolving to include the frontal white matter. AlaRS activity was significantly reduced in five affected individuals with both early infantile-onset and late-onset phenotypes. We suggest that variants in AARS1 result in a broader clinical spectrum than previously appreciated. The predominant form results in early infantile-onset disease with epileptic encephalopathy and deficient myelination. However, a subgroup of affected individuals manifests with late-onset disease and similarly rapid progressive clinical decline. Longitudinal imaging and clinical follow-up will be valuable in understanding factors affecting disease progression and outcome.

Microstructural alterations in medial temporal and frontal white matter tracts are associated with subjective cognitive decline

AbstractBackgroundSubjective cognitive decline (SCD) is a perceived cognitive change prior to objective cognitive deficits, and although it is associated with Alzheimer’s disease (AD) pathology, it likely results from multiple underlying pathologies. We investigated the association of white matter microstructure to SCD as a sensitive and early marker of cognitive decline and quantified the contribution of white matter microstructure separate from amyloidosis.MethodVanderbilt Memory &amp; Aging Project participants with diffusion MRI data and a 45‐item measure of SCD were included (n=237, 73±7 years, 37% female). A subset of participants (n=104) underwent a fasting lumbar puncture for quantification of amyloid‐β (CSF Aβ42). Diffusion MRI data was post‐processed using the free‐water (FW) elimination technique, which allowed quantification of extracellular (FW) and intracellular compartment (fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity) microstructure. Microstructural values were quantified within 11 cognitive‐related white matter tracts, including medial temporal lobe, frontal transcallosal, and fronto‐parietal tracts. General linear modeling related each tract to SCD adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile scores, APOE‐ε4 carrier status, diagnosis, Geriatric Depression Scale scores, and total white matter volume. Competitive model analyses were conducted to determine if white matter microstructural values have a unique role in SCD separate from CSF Aβ42.ResultFW‐corrected radial diffusivity (RDT) was related to SCD in 6 tracts: cingulum bundle (β=3.52x106; p=0.001), inferior longitudinal fasciculus (β=2.77x106; p=0.005), as well as inferior frontal gyrus (IFG) pars opercularis (β=1.98x106; p=0.008), IFG pars triangularis (β=2.69x106; p=0.008), medial frontal gyrus (β=2.46x106; p=0.007), and middle frontal gyrus (β=2.47x106; p=0.014) transcallosal tracts. While CSF Aβ42 was related to SCD in our cohort (β=‐0.021; p=0.020), competitive model analyses revealed that fornix and IFG pars triangularis transcallosal tract RDT contributed unique variance to SCD beyond CSF Aβ42.ConclusionMedial temporal lobe and frontal transcallosal tract microstructure is an important driver of SCD independent of early AD pathology. Given RDT appears to be the most significant predictor of SCD, demyelination may be an early contributor to cognitive decline. These results highlight the value of incorporating multiple biomarkers to help disentangle the mechanistic heterogeneity of SCD as an early stage of cognitive decline.

Frontal interhemispheric structural connectivity, attention, and executive function in children with perinatal stroke.

Perinatal stroke affects ∼1 in 1000 births and concomitant cognitive impairments are common but poorly understood. Rates of Attention Deficit/Hyperactivity Disorder (ADHD) are increased 5–10× and executive dysfunction can be disabling. We used diffusion imaging to investigate whether stroke‐related differences in frontal white matter (WM) relate to cognitive impairments. Anterior forceps were isolated using tractography and sampled along the tract. Resulting metrics quantified frontal WM microstructure. Associations between WM metrics and parent ratings of ADHD symptoms (ADHD‐5 rating scale) and executive functioning (Behavior Rating Inventory of Executive Function (BRIEF)) were explored. Eighty‐three children were recruited (arterial ischemic stroke [AIS] n = 26; periventricular venous infarction [PVI] n = 26; controls n = 31). WM metrics were altered for stroke groups compared to controls. Along‐tract analyses showed differences in WM metrics in areas approximating the lesion as well as more remote differences at midline and in the nonlesioned hemisphere. WM metrics correlated with parental ratings of ADHD and executive function such that higher diffusivity values were associated with poorer function. These findings suggest that underlying microstructure of frontal white matter quantified via tractography may provide a relevant biomarker associated with cognition and behavior in children with perinatal stroke.

Changes in computed tomography perfusion parameters and maximum contrast enhancement in patients having hydrocephalus with a ventriculoperitoneal shunt: a pilot study.

Acute hydrocephalus may decrease cerebral perfusion by increasing intracranial pressure. Computed tomography perfusion (CTP) has become a significant adjunct in evaluating regional and global cerebral blood flow (CBF). To investigate the changes in cerebral perfusion parameters and maximum contrast enhancement (MCE) in patients with hydrocephalus with ventriculoperitoneal shunt (VPS). We performed brain CTP in 45 patients, including those with subarachnoid hemorrhage (SAH)-induced hydrocephalus with VPS (n = 14, G1), hydrocephalus (not related to SAH) with VPS (n = 11, G2), SAH-induced hydrocephalus without VPS (n = 10, G3), and hydrocephalus (not related to SAH) without VPS (n = 10, G4). We measured the cerebral perfusion in the frontal white matter (FWM), centrum semiovale, basal ganglia (BG), and eight cortical lesions of interest and compared the differences in CTP parameters among the groups. Between the four groups, cerebral blood volume and MCE in the left FWM and CBF in the right FWM increased significantly in G1 and G2 who underwent VP shunt compared to G3 and G4, whereas perfusion significantly reduced in G3 and G4 who did not undergo VP shunt compared to G1 and G2. MCE in the left BG significantly increased in G2 and decreased in G3 and G4. SAH-induced hydrocephalus showed a lower perfusion than hydrocephalus (not related to SAH) in FWM. Perfusion changes in patients with hydrocephalus after VP shunt were seen in the FWM and BG, which appears to be the result of the hydrocephalus reducing brain perfusion in the deep part of the brain. We concluded that SAH slows brain perfusion recovery.

Association of Cerebral Blood Flow and Brain Tissue Relaxation Time With Neurodevelopmental Outcomes of Preterm Neonates: Multidelay Arterial Spin Labeling and Synthetic MRI Study.

Both cerebral blood flow (CBF) and brain tissue relaxation times are known to reflect maturation in the neonatal brain. However, we do not yet know if these factors are associated with neurodevelopmental outcomes. The objective of this study was to acquire CBF and relaxation time in preterm neonates, using multidelay arterial spin labeling and synthetic magnetic resonance imaging (MRI), and show their association with later neurodevelopmental outcomes. In this prospective study, preterm neonates were recruited, and multidelay arterial spin labeling and synthetic MRI were performed between September 2017 and December 2018. These neonates underwent the Bayley Scales of Infant Development test at 18 months of age, and both cognitive and motor outcome scores were measured. Transit time-corrected CBF and T1 and T2 relaxation time values were measured for different brain regions. The measured values were correlated with gestational age (GA) at birth and corrected GA at the MRI scan. Simple and multiple linear regression analyses were performed for the measured values and neurodevelopmental outcome scores. Forty-nine neonates (median [interquartile range] GA, 30 [2] weeks, 209 [17] days; 28 boys) underwent MRI scans at or near term-equivalent age (median [interquartile range] corrected GA, 37 [2] weeks, 258 [14] days). Transit time-corrected CBF (coefficient, 0.31-0.59) and relaxation time (coefficient, -0.39 to -0.86) values showed significant correlation with corrected GA but not with GA. After controlling for GA, the frontal white matter CBF in preterm neonates showed a negative relationship with cognitive outcome scores (β = -0.97; P = 0.029). Frontal white matter T1 relaxation times showed a positive relationship with cognitive outcome scores (β = 0.03; P = 0.025) after controlling for GA. Higher CBF values and lower T1 relaxation times in frontal white matter were associated with poorer cognitive outcomes. As quantitative neuroimaging markers, CBF and relaxation times may help predict neurodevelopmental outcomes in preterm neonates.

Extramedullary Acute Myeloid Leukemia: Testicular Myeloid Leukemia, Leukemia Cutis with Leptomeningeal Involvement

Extramedullary Acute Myeloid Leukemia: Testicular myeloid leukemia, leukemia cutis with leptomeningeal involvementZ Saeed, H Aslam, A Weil, M MuzaffarMyeloid sarcoma also called granulocytic sarcoma, myeloblastoma, or chloroma is an extramedullary tumor of immature granulocytic cells. Extramedullary soft tissue manifestations are relatively rare in hematological malignancies. One of the rarest manifestations is myeloid sarcoma (MS). MS develops as part of acute myeloid leukemia, myeloproliferative neoplasm, or myelodysplastic syndrome or at relapse, especially following allogeneic hematopoietic stem cell transplant. Demographically, it has a slight male predominance with a male to female ratio of 1.2: 1. It may occur at any age and any site in the body leading to varied clinical presentations. The most reported sites are lymph nodes, skin and soft tissues, bone, testes, gastrointestinal tract, and peritoneum.44 year old male with past medical history of diabetes mellitus type 2 and morbid obesity presented with right testicular pain and swelling and underwent radical orchiectomy. Pathology reported seminoma and received adjuvant Carboplatin for pT3 disease. He developed left testicular pain and swelling 2 months later and underwent left radical orchiectomy. Pathology reported CD4+, CD56+ high grade hematopoietic neoplasm. It was sent for second opinion to NIH and was consistent with myeloid sarcoma with monoblastic features. Repeat evaluation of right testicular specimen was CD45+. Bone marrow biopsy showed normocellular marrow with multilineage hematopoiesis. PET scan showed hyper metabolic activity in the right hemi scrotum, widespread osseous areas of increased uptake and 3 soft tissue nodules within the subcutaneous tissues of the left abdominal wall. FNA of the subcutaneous nodule showed CD56 positive monocytoid cells. Induction chemotherapy with 7+3 (cytarabine 200 mg/m2, daunorubicin 60mg/m2) with gemtuzumab 3mg/m2 on day 1, 4, 7 was completed. Cerebrospinal fluid studies (CSF) showed monoblastic/monocytic proliferation and received intrathecal (IT) chemotherapy alternating between methotrexate and cytarabine every week. CSF studies were cleared after 2 IT chemotherapy. Patient remained in the hospital for 87 days due to poor count recovery and development of pulmonary embolism. Myeloid mutation screening identified a mutation in NRASG13D. Repeat PET scan showed 7 areas of hypermetabolic foci involving nodular densities of bilateral lower anterior abdominal wall. One of the lesion was biopsied that was negative. He completed 2 cycles of high dose cytarabine for consolidation but had repeated hospital admissions and therapy was switched to azacytidine and venetoclax. Patient was evaluated by bone marrow transplant team. He had disease progression at tenth month when he presented with severe back pain and lower extremity weakness. MRI brain and spine showed new patchy T2 hyperintense signal in the right frontal white matter, increased number and size of marrow replacing lesions throughout the visualized skeleton. Patient underwent bone biopsy that showed >90% marrow involvement (sheets of infiltrative cells with identical phenotype. Positive for CD56 (>90% of marrow cellularity), CD4 and lysozyme. Hospital course was complicated with renal failure, electrolytes imbalance and hemodynamically instability requiring vasopressor support. Discussions were held for re-induction with CLAG (cladribine 5mg/m2, and cytarabine 2gm/m2) vs best supportive care. Patient decided to pursue comfort care and passed away peacefully.The uniqueness of this case is the myeloid sarcoma of testes as initial presentation with normal bone marrow. Misdiagnosis is not uncommon and can delay the appropriate treatment. Extra medullary involvement from leukemia is very aggressive and needs high suspicious and prompt treatment. Systemic chemotherapy using AML-like regimens should be commenced early, even in non leukemic disease. Allogeneic hematopoietic stem cell transplantation has demonstrated promising results, particularly in patients who achieved complete remission with AML-induction protocols, and recent advances in genetic profiling may enable the development of novel targeted therapies. Prospective multicenter controlled trials are required to further refine management decisions and investigate the role of novel targeted therapies. DisclosuresNo relevant conflicts of interest to declare.

Novel CSF1R variant in adult-onset leukoencephalopathy masquerading as frontotemporal dementia: a follow-up study

ABSTRACT Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare white matter degenerative disease manifesting as progressive cognitive decline, pyramidal, and extrapyramidal features resulting from mutations in the colony-stimulating factor-1 receptor (CSF1R) gene. We describe a sporadic case of a young man who developed five months history of progressive cognitive decline with predominant neuropsychiatric symptoms, suggestive of frontotemporal dementia. Brain magnetic resonance imaging (MRI) showed bilateral frontotemporal atrophy, high signal intensities in frontal and high parietal deep white matter with persistent diffusion restriction on follow-up imaging. Genetics showed a novel heterozygous mutation in CSF1R gene confirming the diagnosis of ALSP. Being a rare disease, and given its particular adult-onset presentation especially presenile cognitive impairment, it can pose a unique diagnostic challenge. The study highlights the importance of recognizing the disease early and broadens the clinical, genetic, and imaging spectrum of CSF1R gene mutation.

GP.4 Can Quantitative Susceptibility Mapping Help Diagnose and Predict Recovery of Concussion in Children?

Background: Quantitative susceptibility mapping (QSM) is an MR sequence that has potential as a biomarker in concussion. We compared QSM in pediatric concussion patients versus a comparison group of children with orthopedic injuries (OI) and assessed QSM’s performance relative to the current clinical benchmark (5P risk score) for predicting persistent postconcussion symptoms (PPCS). Methods: Children (N=967) aged 8-16.99 years with either concussion or OI were prospectively recruited from 5 Canadian centers. Participants completed QSM at a post-acute assessment 2-33 days post-injury. QSM z-score metrics for 9 regions of interest (ROI) were derived from 371 children (concussion=255, OI=116). PPCS at 1-month post-injury was defined using reliable change methods. Results: The concussion and OI groups did not differ significantly in QSM across ROI. Increased frontal white matter (WM) susceptibility predicted reliable increases in parent-rated cognitive symptoms (p=0.001). Together, frontal WM susceptibility and the 5P risk score were better at predicting persistent cognitive symptoms than the 5P risk score alone (p=0.0021). AUC were 0.71(95%CI: 0.62-0.80) for frontal WM susceptibility, 0.67(95%CI: 0.56-0.78) for the 5P risk score, and 0.73(95%CI: 0.64-0.82) for both. Conclusions: This is the first study to demonstrate a potential imaging biomarker that predicts persistent symptoms in children with concussion compared to the current clinical benchmark.