Subcortical Matter Research Articles

Clinical, Cortical, Subcortical, and White Matter Features of Right Temporal Variant FTD.

Eight patients with right temporal variant FTD were prospectively recruited and underwent a standardised neuropsychological assessment, clinical MRI, and quantitative neuroimaging. Our voxelwise grey analyses captured bilateral anterior and mesial temporal grey matter atrophy with a clear right-sided predominance. Bilateral hippocampal involvement was also observed, as well as disease burden in the right insular and opercula regions. White matter integrity alterations were also bilateral in anterior temporal and sub-insular regions with a clear right-hemispheric predominance. Extra-temporal white matter alterations have also been observed in orbitofrontal and parietal regions. Significant bilateral but right-predominant thalamus, putamen, hippocampus, and amygdala atrophy was identified based on subcortical segmentation. The clinical profile of our patients was dominated by progressive indifference, decline in motivation, loss of interest in previously cherished activities, incremental social withdrawal, difficulty recognising people, progressive language deficits, increasingly rigid routines, and repetitive behaviours. Right temporal variant FTD has an insidious onset and may be mistaken for depression at symptom onset. It manifests in a combination of apathy, language, and behavioural features. Quantitative MR imaging captures a characteristic bilateral but right-predominant temporal imaging signature with extra-temporal frontal and parietal involvement.

Hippocampal hub failure is linked to long-term memory impairment in anti-NMDA-receptor encephalitis: insights from structural connectome graph theoretical network analysis

BackgroundAnti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is characterized by distinct structural and functional brain alterations, predominantly affecting the medial temporal lobes and the hippocampus. Structural connectome analysis with graph-based investigations of network properties allows for an in-depth characterization of global and local network changes and their relationship with clinical deficits in NMDAR encephalitis.MethodsStructural networks from 61 NMDAR encephalitis patients in the post-acute stage (median time from acute hospital discharge: 18 months) and 61 age- and sex-matched healthy controls (HC) were analyzed using diffusion-weighted imaging (DWI)-based probabilistic anatomically constrained tractography and volumetry of a selection of subcortical and white matter brain volumes was performed. We calculated global, modular, and nodal graph measures with special focus on default-mode network, medial temporal lobe, and hippocampus. Pathologically altered metrics were investigated regarding their potential association with clinical course, disease severity, and cognitive outcome.ResultsPatients with NMDAR encephalitis showed regular global graph metrics, but bilateral reductions of hippocampal node strength (left: p = 0.049; right: p = 0.013) and increased node strength of right precuneus (p = 0.013) compared to HC. Betweenness centrality was decreased for left-sided entorhinal cortex (p = 0.042) and left caudal middle frontal gyrus (p = 0.037). Correlation analyses showed a significant association between reduced left hippocampal node strength and verbal long-term memory impairment (p = 0.021). We found decreased left (p = 0.013) and right (p = 0.001) hippocampal volumes that were associated with hippocampal node strength (left p = 0.009; right p < 0.001).ConclusionsFocal network property changes of the medial temporal lobes indicate hippocampal hub failure that is associated with memory impairment in NMDAR encephalitis at the post-acute stage, while global structural network properties remain unaltered. Graph theory analysis provides new pathophysiological insight into structural network changes and their association with persistent cognitive deficits in NMDAR encephalitis.

Limbic Network and Papez Circuit Involvement in ALS: Imaging and Clinical Profiles in GGGGCC Hexanucleotide Carriers in C9orf72 and C9orf72-Negative Patients.

Background: While frontotemporal involvement is increasingly recognized in Amyotrophic lateral sclerosis (ALS), the degeneration of limbic networks remains poorly characterized, despite growing evidence of amnestic deficits, impaired emotional processing and deficits in social cognition. Methods: A prospective neuroimaging study was conducted with 204 individuals with ALS and 111 healthy controls. Patients were stratified for hexanucleotide expansion status in C9orf72. A deep-learning-based segmentation approach was implemented to segment the nucleus accumbens, hypothalamus, fornix, mammillary body, basal forebrain and septal nuclei. The cortical, subcortical and white matter components of the Papez circuit were also systematically evaluated. Results: Hexanucleotide repeat expansion carriers exhibited bilateral amygdala, hypothalamus and nucleus accumbens atrophy, and C9orf72 negative patients showed bilateral basal forebrain volume reductions compared to controls. Both patient groups showed left rostral anterior cingulate atrophy, left entorhinal cortex thinning and cingulum and fornix alterations, irrespective of the genotype. Fornix, cingulum, posterior cingulate, nucleus accumbens, amygdala and hypothalamus degeneration was more marked in C9orf72-positive ALS patients. Conclusions: Our results highlighted that mesial temporal and parasagittal subcortical degeneration is not unique to C9orf72 carriers. Our radiological findings were consistent with neuropsychological observations and highlighted the importance of comprehensive neuropsychological testing in ALS, irrespective of the underlying genotype.

Levels of neurotrophins in the brain of female rats in an experimental model of malignant tumor growth under conditions of hypothyroidism

Objective. Studying the levels of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF-β), and neurotrophin 3 (NT3) in the cerebral cortex and subcortical substance of female rats in an experimental model of extracerebral growth of malignant tumor under conditions of induced hypothyroidism.Materials and methods. An experiment was performed on 47 white non-linear female rats: 10 rats each in the intact group, control group 1 (induced hypothyroidism), control group 2 (subcutaneous growth of Guerin’s carcinoma), main group (combination of pathologies); 7 rats in the group with subcutaneous tumor growth to assess life expectancy. Hypothyroidism was induced by per os administration of thiamazole (mercazolil, Akrikhin, Russia), daily dose of 2.5 mg/100 g of body weight, course of 30 days; total thyroxine and thyroid stimulating hormone were determined in blood serum by RIA (Immunotech, Czech Republic). When persistent hypothyroidism was achieved, Guerin’s carcinoma was transplanted under the skin as standard. Aſter decapitation on the 18th day aſter transplantation, the content of BDNF, NGF-β, NT3 (R&amp;D System, RayBiotech, USA) was determined in 10 % homogenates of the cortex and subcortical substance subcortex of the brain (R&amp;D System, RayBiotech, USA).Results. In the cortex in control groups 1 and 2, the level of BDNF was 2.6- and 1.6-fold lower, respectively, and NGF-β was 2.2-fold higher on average than in the intact group. NT3 levels in the control group 1 were 3.0- and 1.6-fold lower in the cortex and subcortical substance, respectively. In the control group 2, the levels of NT3 and NGF-β were higher in the subcortical matter than in the intact group by 2.4-fold and 3.1-fold, respectively. In the cortex and subcortical substance in the main group, only NGF-β levels were higher on average by 1.7 times, with values being intermediate between the corresponding values in control groups 1 and 2.Conclusion. Changes in the levels of all neurotrophins in hypothyroidism were most pronounced in the cortex, while in independent tumor growth, NGF-β in the cortex and subcortical substance and NT3 only in subcortical substance changed the most. When the pathologies were combined, only NGF-β was altered in the cortex and subcortical substance. Apparently, there is an interaction of the tumor and the CNS with changes in the balance of regulatory signals in the subcortical areas of the brain, that reflecting the connection with the biological characteristics of an active or inhibited (in presence of hypothyroidism) tumor growth.

Repeatability of neurite orientation dispersion and density imaging in patients with traumatic brain injury.

The aim of this study was to assess the repeatability of neurite orientation dispersion and density imaging in healthy controls (HCs) and traumatic brain injury (TBI). Seventeen HCs and 48 TBI patients were scanned twice over 18weeks with diffusion imaging. Orientation dispersion (ODI), neurite density (NDI), and the fraction of isotropic diffusion (F-ISO) were quantified in regions of interest (ROIs) from a gray matter, subcortical, and white matter atlas and compared using the coefficient of variation for repeated measures (CVrep ), which quantifies the expected percent change on repeated measurement. We used a modified signed likelihood ratio test (M-SLRT) to compare the CVrep between groups in each ROI while correcting for multiple comparisons. NDI exhibited excellent repeatability in both groups; the only group difference was found in the fusiform gyrus, where HCs exhibited better repeatability (M-SLRT=9.463, p=.0021). ODI also had excellent repeatability in both groups, although repeatability was significantly better in HCs in 16 cortical ROIs (p<.0022) and in the bilateral white matter and bilateral cortex (p<.0027). F-ISO exhibited relatively poor repeatability in both groups, with few group differences. Overall, the repeatability of the NDI, ODI, and F-ISO metrics over an 18-week period is acceptable for assessing the effects of behavioral or pharmacological interventions, though caution is advised when assessing F-ISO changes over time.

Disappearance of hemichorea as the initial presentation of moyamoya disease after revascularization surgery regardless of residual hypoperfusion evaluated by quantitative N-isopropyl-p-123I-iodoamphetamine SPECT

Background and importanceAlthough hypoperfusion of the basal ganglia or the frontal subcortical matter is suspected, the pathology of chorea in moyamoya disease remains unclarified. Herein, we report a case of moyamoya disease presenting with hemichorea and evaluate pre- and postoperative perfusion using single photon emission computed tomography with N-isopropyl-p-123I-iodoamphetamine (123I-IMP SPECT). Clinical presentationAn 18-year-old woman presented with choreic movement of her left limbs. Magnetic resonance imaging revealed an ivy sign, and 123I-IMP SPECT demonstrated decreased cerebral blood flow (CBF) and cerebral vascular reserve (CVR) values in the right hemisphere. The patient underwent direct and indirect revascularization surgery to improve cerebral hemodynamic impairment. The choreic movements entirely resolved immediately after surgery. Although CBF and CVR values in the ipsilateral hemisphere demonstrated by quantitative SPECT increased, these did not reach the normal values threshold. ConclusionChoreic movement in moyamoya disease may be related to cerebral hemodynamic impairment. Further studies are required to elucidate its pathophysiological mechanisms.

Nonverbal memory tests revisited: Neuroanatomical correlates and differential influence of biasing cognitive functions

The detection of right temporal lobe dysfunction with nonverbal memory tests has remained difficult in the past. Reasons for this might be the potential influence of other biasing cognitive functions such as executive functions or the verbalisability of nonverbal material. The aim of this study was to investigate three classic nonverbal memory tests by identifying their neuroanatomical correlates with lesion-symptom mapping (LSM) and by probing their independence from verbal encoding abilities and executive functions.In a cohort of 119 patients with first-time cerebrovascular accident, memory performance was assessed in the Nonverbal Learning and Memory Test for Routes (NLMTR), the Rey Complex Figure Test (RCFT), and the Visual Design Learning Test (VDLT). Calculating multivariate LSM, we identified crucial brain structures for these three nonverbal memory tests. Behavioural analyses were performed to assess the impact of executive functions and verbal encoding abilities with regression analyses and likelihood-ratio tests.LSM revealed for the RCFT mainly right-hemispheric frontal, insular, subcortical, and white matter structures and for the NLMTR right-hemispheric temporal (hippocampus), insular, subcortical, and white matter structures. The VDLT did not reach significance in LSM analyses. Behavioural results showed that amongst the three nonverbal memory tests the impact of executive functions was most pronounced for RCFT, and the impact of verbal encoding abilities was most important in VDLT. Likelihood-ratio tests confirmed that only for NLMTR did the goodness of fit not significantly improve by adding executive functions or verbal encoding abilities.These results suggest that amongst the three nonverbal memory tests the NLMTR, as a spatial navigation test, could serve as the most suitable marker of right-hemispheric temporal lobe functioning, with the right hippocampus being involved only in this test. In addition, the behavioural results propose that only NLMTR seems mostly unaffected by executive functions and verbal encoding abilities.

Infarct Topography and Reperfusion Injury After Endovascular Thrombectomy for Large Vessel Occlusion Stroke (S20.002)

<h3>Objective:</h3> To quantify region-specific volumes of infarcted tissue on MRI pre-endovascular thrombectomy (EVT), understand their importance for reperfusion injury and hemorrhagic transformation (HT), and identify associations with clinical and imaging characteristics. <h3>Background:</h3> With continued expansion in indications for EVT, understanding the pathophysiology of reperfusion injury and HT becomes increasingly important. Pre-EVT infarct topography may have implications for treatment decisions acutely (e.g. stenting), and with post EVT care (e.g. antithrombotics). <h3>Design/Methods:</h3> Patients were identified from a prospectively maintained database. Each patient’s diffusion weighted sequence underwent manual infarct delineation and was registered to a standard space for overlay with cortical, subcortical, and white matter atlases. HT was defined as ECASS PH1 or PH2. Variables with p&lt;0.10 in univariate analyses were included in multivariable models. <h3>Results:</h3> 165 participants [median age 69 (IQR 56–79), 56% women] were identified. Intravenous alteplase was administered to 52%; 70% achieved TICI 2b-3 reperfusion. HT occurred in 8%. The distribution of pre-EVT infarcts was 48% (38–60%) white matter, 23% (6–47%) cortex, and 15% (4–28%) basal ganglia. Pre-EVT infarct volumes [median (IQR)] were 22 cc (12–43 cc) for total, 11 cc (6–19 cc) for white matter, 5 cc (1–19 cc) for cortex, and 3 cc (1–6 cc) for basal ganglia infarct. Paramagnetic sequences showed 3% had petechial hemorrhage and 40% had susceptibility vessel sign. Basal ganglia infarct volume was independently associated with HT (OR=1.342, 95%CI=1.002,1.797) in a model including white matter infarct volume, cortex infarct volume, smoking, and puncture-to-recanalization time. Basal ganglia infarct volume was linked to susceptibility vessel sign (Beta=0.233, p=0.006) and NIHSS (Beta=0.220, p=0.012), when controlling for total infarct volume. <h3>Conclusions:</h3> Greater basal ganglia infarct volume was associated with a higher risk of HT when accounting for infarct volumes in other regions. Susceptibility vessel sign was associated with basal ganglia infarct volume, which may be related to acute middle cerebral artery perforator occlusion. <b>Disclosure:</b> Dr. Regenhardt has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Rapid Medical. Dr. Regenhardt has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Johnson and Bell Trial Lawyers. The institution of Dr. Regenhardt has received research support from National Institutes of Health. The institution of Dr. Regenhardt has received research support from Society of Vascular and Interventional Neurology. The institution of Dr. Regenhardt has received research support from Heitman Foundation. Dr. Bonkhoff has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for NeuroImage Clinical (Elsevier). Dr. Schirmer has nothing to disclose. Dr. Das has nothing to disclose. Dr. Dmytriw has nothing to disclose. Dr. Vranic has nothing to disclose. Dr. Gupta has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for •

Abstract Number ‐ 34: Basal ganglia infarct volume and risk of hemorrhagic transformation after endovascular thrombectomy

Introduction As more large vessel occlusion stroke patients are treated with endovascular thrombectomy (EVT), understanding the pathophysiology of reperfusion injury and the risks of hemorrhagic transformation (HT) are increasingly important. Pre‐EVT infarct topography may have implications for acute interventional treatments such as stenting, and post thrombectomy care such as antithrombotic choice. We sought to quantify region‐specific volumes of infarcted tissue on pre‐EVT MRI, understand their importance for HT, and identify associations with clinical and imaging characteristics. Methods Patients with pre‐EVT MRI were identified retrospectively from a prospectively maintained database. Each patient’s diffusion weighted sequence underwent manual infarct delineation and was registered to a standard space for overlay with cortical, subcortical, and white matter atlases. Structure‐specific lesion volumes were determined. HT was defined as PH1 or PH2 hemorrhage by ECASS criteria. Variables with p&lt; 0.10 in univariate analyses were included in multivariable models. Logistic regression was performed for associations with hemorrhagic transformation and linear regressions for infarct volumes. Results 165 participants [median age 69 years (interquartile range, IQR 56–79), 56% women] were identified. Risk factors included hypertension (70%), diabetes (20%), atrial fibrillation (34%), and prior stroke/TIA (13%). 52% were treated with intravenous alteplase; 70% achieved TICI 2b‐3 reperfusion. HT occurred in 8%. Pre‐EVT infarct volumes [median (IQR)] were 22 cc (12‐43 cc) for total, 11 cc (6‐19 cc) for white matter, 5 cc (1‐19 cc) for cortex, and 3 cc (1‐6 cc) for basal ganglia. Pre‐EVT infarcts [median (IQR)] were made up of 48% (38‐60%) white matter, 23% (6‐47%) cortex, and 15% (4‐28%) basal ganglia. Paramagnetic sequences showed 3% had petechial hemorrhage and 40% had susceptibility vessel sign. Basal ganglia infarct volume was independently associated with HT (OR = 1.342, 95%CI = 1.002,1.797) in a model including white matter infarct volume, cortex infarct volume, smoking, and puncture‐recanalization time. Basal ganglia infarct volume was linked to susceptibility vessel sign (Beta = 0.233, p = 0.006) and NIHSS (Beta = 0.220, p = 0.012), when controlling for total infarct volume. Conclusions In this cohort, greater basal ganglia infarct volume was associated with a higher risk of hemorrhagic transformation, even when accounting for infarct volume in other regions. Susceptibility vessel sign was associated with basal ganglia infarct volume, which may be related to acute middle cerebral artery thrombus occlusion of perforators. These findings require further study in larger cohorts.

Abstract TP128: Hemorrhagic Transformation After Endovascular Thrombectomy Is Associated With Basal Ganglia Infarct Volume

Introduction: With continued expansion in indications for endovascular thrombectomy (EVT), understanding the pathophysiology of reperfusion injury and the risks of hemorrhagic transformation (HT) becomes increasingly important. Pre-EVT infarct topography may have implications for treatment decisions acutely (e.g. stenting), and with post EVT care (e.g. antithrombotics). We sought to quantify region-specific volumes of infarcted tissue on pre-EVT MRI, understand their importance for HT, and identify associations with clinical and imaging characteristics. Methods: Patients with pre-EVT MRI were identified from a prospectively maintained database. Each patient’s diffusion weighted sequence underwent manual infarct delineation and was registered to a standard space for overlay with cortical, subcortical, and white matter atlases. HT was defined as ECASS PH1 or PH2. Variables with p&lt;0.10 in univariate analyses were included in multivariable models. Results: A total of 165 participants [median age 69 (IQR 56-79), 56% women] were identified. Intravenous alteplase was administered to 52%; 70% achieved TICI 2b-3 reperfusion. HT occurred in 8%. The distribution of pre-EVT infarcts was 48% (38-60%) white matter, 23% (6-47%) cortex, and 15% (4-28%) basal ganglia. Pre-EVT infarct volumes [median (IQR)] were 22 cc (12-43 cc) for total, 11 cc (6-19 cc) for white matter, 5 cc (1-19 cc) for cortex, and 3 cc (1-6 cc) for basal ganglia infarct. Paramagnetic sequences showed 3% had petechial hemorrhage and 40% had susceptibility vessel sign. Basal ganglia infarct volume was independently associated with HT (OR=1.342, 95%CI=1.002,1.797) in a model including white matter infarct volume, cortex infarct volume, smoking, and puncture-to-recanalization time. Basal ganglia infarct volume was linked to susceptibility vessel sign (Beta=0.233, p=0.006) and NIHSS (Beta=0.220, p=0.012), when controlling for total infarct volume. Conclusions: Greater basal ganglia infarct volume was associated with a higher risk of HT when accounting for infarct volumes in other regions. Susceptibility vessel sign was associated with basal ganglia infarct volume, which may be related to acute middle cerebral artery perforator occlusion.

Structural Relationship between Cerebral Gray and White Matter Alterations in Degenerative Cervical Myelopathy.

Patients with degenerative cervical myelopathy (DCM) undergo adaptive supraspinal changes. However, it remains unknown how subcortical white matter changes reflect the gray matter loss. The current study investigated the interrelationship between gray matter and subcortical white matter alterations in DCM patients. Cortical thickness of gray matter, as well as the intra-cellular volume fraction (ICVF) of subcortical whiter matter, were assessed in a cohort of 44 patients and 17 healthy controls (HCs). The results demonstrated that cortical thinning of sensorimotor and pain related regions is associated with more severe DCM symptoms. ICVF values of subcortical white matter underlying the identified regions were significantly lower in study patients than in HCs. The left precentral gyrus (r = 0.5715, p < 0.0001), the left supramarginal gyrus (r = 0.3847, p = 0.0099), the left postcentral gyrus (r = 0.5195, p = 0.0003), the right superior frontal gyrus (r = 0.3266, p = 0.0305), and the right caudal (r = 0.4749, p = 0.0011) and rostral anterior cingulate (r = 0.3927, p = 0.0084) demonstrated positive correlations between ICVF and cortical thickness in study patients, but no significant correlations between ICVF and cortical thickness were observed in HCs. Results from the current study suggest that DCM may cause widespread gray matter alterations and underlying subcortical neurite loss, which may serve as potential imaging biomarkers reflecting the pathology of DCM.

Pulse pressure trajectories predict brain microstructure in community-dwelling older adults: Associations with executive function and modification by APOE.

Effects of chronic arterial stiffness on brain aging remain unclear. We, therefore, examined whether long-term trajectories of pulse pressure (PP) predicted brain microstructure, microstructure mediated PP-executive function associations, and APOE genotype modified PP-microstructure associations. We examined associations of PP trajectories with brain microstructure measured using restriction spectrum imaging in 146 community-dwelling older adults, whether microstructure mediated PP trajectory-executive function associations, and whether PP-restriction spectrum imaging correlations were modified by APOE-ε4 status. Participants with trajectories of high PP had lower restricted isotropic diffusion (RI) compared to those with low PP trajectories and PP-executive function associations were mediated by subcortical and white matter RI. High PP more strongly correlated with lower RI and higher hindered diffusion among APOE-ε4 carriers than non-carriers. Prolonged elevated PP predicts microstructural abnormalities which may contribute to impaired executive function. APOE-ε4 carriers may be most vulnerable to the adverse effects of PP on brain microstructure.

Fusion of quantitative susceptibility maps and T1-weighted images improve brain tissue contrast in primates

Recent progress in quantitative susceptibility mapping (QSM) has enabled the accurate delineation of submillimeter-scale subcortical brain structures in humans. However, the simultaneous visualization of cortical, subcortical, and white matter structure remains challenging, utilizing QSM data solely. Here we present TQ-SILiCON, a fusion method that enhances the contrast of cortex and subcortical structures and provides an excellent white matter delineation by combining QSM and conventional T1-weighted (T1w) images. In this study, we first applied QSM in the macaque monkey to map iron-rich subcortical structures. Implementing the same QSM acquisition and analysis methods allowed a similar accurate delineation of subcortical structures in humans. However, the QSM contrast of white and cortical gray matter was not sufficient for appropriate segmentation. Applying automatic brain tissue segmentation to TQ-SILiCON images of the macaque improved the classification of subcortical brain structures as compared to the single T1 contrast by maintaining an excellent white to cortical gray matter contrast. Furthermore, we validated our dual-contrast fusion approach in humans and similarly demonstrated improvements in automated segmentation of the cortex and subcortical structures. We believe the proposed contrast will facilitate translational studies in nonhuman primates to investigate the pathophysiology of neurodegenerative diseases that affect subcortical structures such as the basal ganglia in humans.

Altered high-energy phosphate and membrane metabolism in Pelizaeus-Merzbacher disease using phosphorus magnetic resonance spectroscopy.

Pelizaeus–Merzbacher disease is an X-linked recessive leucodystrophy of the central nervous system caused by mutations affecting the major myelin protein, proteolipid protein 1. The extent of the altered in vivo neurochemistry of protein, proteolipid protein 1 duplications, the most common form of Pelizaeus–Merzbacher disease, is, however, poorly understood. Phosphorus magnetic resonance spectroscopy is the only in vivo technique that can assess the biochemistry associated with high-energy phosphate and membrane phospholipid metabolism across different cortical, subcortical and white matter areas. In this cross-sectional study, whole-brain, multi-voxel phosphorus magnetic resonance spectroscopy was acquired at 3 T on 14 patients with Pelizaeus–Merzbacher disease with protein, proteolipid protein 1 duplications and 23 healthy controls (all males). Anabolic and catabolic levels of membrane phospholipids (phosphocholine and phosphoethanolamine, and glycerophosphoethanolamine and glycerophosphocholine, respectively), as well as phosphocreatine, inorganic orthophosphate and adenosine triphosphate levels relative to the total phosphorus magnetic resonance spectroscopy signal from 12 different cortical and subcortical areas were compared between the two groups. Independent of brain area, phosphocholine, glycerophosphoethanolamine and inorganic orthophosphate levels were significantly lower (P = 0.0025, P < 0.0001 and P = 0.0002) and phosphocreatine levels were significantly higher (P < 0.0001) in Pelizaeus–Merzbacher disease patients compared with controls. Additionally, there was a significant group-by-brain area interaction for phosphocreatine with post-hoc analyses demonstrating significantly higher phosphocreatine levels in patients with Pelizaeus–Merzbacher disease compared with controls across multiple brain areas (anterior and posterior white matter, superior parietal lobe, posterior cingulate cortex, hippocampus, occipital cortex, striatum and thalamus; all P ≤ 0.0042). Phosphoethanolamine, glycerophosphoethanolamine and adenosine triphosphate levels were not significantly different between groups. For the first-time, widespread alterations in phosphorus magnetic resonance spectroscopy metabolite levels of Pelizaeus–Merzbacher disease patients are being reported. Specifically, increased high-energy phosphate storage levels of phosphocreatine concomitant with decreased inorganic orthophosphate across multiple areas suggest a widespread reduction in the high-energy phosphate utilization in Pelizaeus–Merzbacher disease, and the membrane phospholipid metabolite deficits suggest a widespread degradation in the neuropil content/maintenance of patients with Pelizaeus–Merzbacher disease which includes axons, dendrites and astrocytes within cortex and the myelin microstructure and oligodendrocytes within white matter. These results provide greater insight into the neuropathology of Pelizaeus–Merzbacher disease both in terms of energy expenditure and membrane phospholipid metabolites. Future longitudinal studies are warranted to investigate the utility of phosphorus magnetic resonance spectroscopy as surrogate biomarkers in monitoring treatment intervention for Pelizaeus–Merzbacher disease.

Structural Brain Imaging Predicts Individual-Level Task Activation Maps Using Deep Learning.

Accurate individual functional mapping of task activations is a potential tool for biomarker discovery and is critically important for clinical care. While structural imaging does not directly map task activation, we hypothesized that structural imaging contains information that can accurately predict variations in task activation between individuals. To this end, we trained a convolutional neural network to use structural imaging (T1-weighted, T2-weighted, and diffusion tensor imaging) to predict 47 different functional MRI task activation volumes across seven task domains. The U-Net model was trained on 591 subjects and then subsequently tested on 122 unrelated subjects. The predicted activation maps correlated more strongly with their actual maps than with the maps of the other test subjects. An ablation study revealed that a model using the shape of the cortex alone or the shape of the subcortical matter alone was sufficient to predict individual-level differences in task activation maps, but a model using the shape of the whole brain resulted in markedly decreased performance. The ablation study also showed that the additional information provided by the T2-weighted and diffusion tensor imaging strengthened the predictions as compared to using the T1-weighted imaging alone. These results indicate that structural imaging contains information that is predictive of inter-subject variability in task activation mapping and that cortical folding patterns, as well as microstructural features, could be a key component to linking brain structure to brain function.

The relationship between isolated hypertension with brain volumes in UK Biobank.

BackgroundHypertension is a well‐established risk factor for cognitive impairment, brain atrophy, and dementia. However, the relationship of other types of hypertensions, such as isolated hypertension on brain health and its comparison to systolic‐diastolic hypertension (where systolic and diastolic measures are high), is still relatively unknown. Due to its increased prevalence, it is important to investigate the impact of isolated hypertension to help understand its potential impact on cognitive decline and future dementia risk. In this study, we compared a variety of global brain measures between participants with isolated hypertension to those with normal blood pressure (BP) or systolic‐diastolic hypertension using the largest cohort of healthy individuals.MethodsUsing the UK Biobank cohort, we carried out a cross‐sectional study using 29,775 participants (mean age 63 years, 53% female) with BP measurements and brain magnetic resonance imaging (MRI) data. We used linear regression models adjusted for multiple confounders to compare a variety of global, subcortical, and white matter brain measures. We compared participants with either isolated systolic or diastolic hypertension with normotensives and then with participants with systolic‐diastolic hypertension.ResultsThe results showed that participants with isolated systolic or diastolic hypertension taking BP medications had smaller gray matter but larger white matter microstructures and macrostructures compared to normotensives. Isolated systolic hypertensives had larger total gray matter and smaller white matter traits when comparing these regions with participants with systolic‐diastolic hypertension.ConclusionsThese results provide support to investigate possible preventative strategies that target isolated hypertension as well as systolic‐diastolic hypertension to maintain brain health and/or reduce dementia risk earlier in life particularly in white matter regions.

Clusters of anatomical disease-burden patterns in ALS: a data-driven approach confirms radiological subtypes

Amyotrophic lateral sclerosis (ALS) is associated with considerable clinical heterogeneity spanning from diverse disability profiles, differences in UMN/LMN involvement, divergent progression rates, to variability in frontotemporal dysfunction. A multitude of classification frameworks and staging systems have been proposed based on clinical and neuropsychological characteristics, but disease subtypes are seldom defined based on anatomical patterns of disease burden without a prior clinical stratification. A prospective research study was conducted with a uniform imaging protocol to ascertain disease subtypes based on preferential cerebral involvement. Fifteen brain regions were systematically evaluated in each participant based on a comprehensive panel of cortical, subcortical and white matter integrity metrics. Using min–max scaled composite regional integrity scores, a two-step cluster analysis was conducted. Two radiological clusters were identified; 35.5% of patients belonging to ‘Cluster 1’ and 64.5% of patients segregating to ‘Cluster 2’. Subjects in Cluster 1 exhibited marked frontotemporal change. Predictor ranking revealed the following hierarchy of anatomical regions in decreasing importance: superior lateral temporal, inferior frontal, superior frontal, parietal, limbic, mesial inferior temporal, peri-Sylvian, subcortical, long association fibres, commissural, occipital, ‘sensory’, ‘motor’, cerebellum, and brainstem. While the majority of imaging studies first stratify patients based on clinical criteria or genetic profiles to describe phenotype- and genotype-associated imaging signatures, a data-driven approach may identify distinct disease subtypes without a priori patient categorisation. Our study illustrates that large radiology datasets may be potentially utilised to uncover disease subtypes associated with unique genetic, clinical or prognostic profiles.

Abstract 12: CT Perfusion For Lesion-Symptom Mapping In Emergent Large Vessel Occlusion

Introduction: Selection criteria for endovascular thrombectomy (EVT) for emergent large-vessel occlusion (ELVO) stroke increasingly rely on CT perfusion (CTP) findings at presentation. While perfusion imaging is used to estimate the likelihood of deriving long-term functional benefit from EVT, there is comparatively little data on how perfusion deficits relate to domains of neurological function. Here, we investigated region-specific hypoperfusion as a driver of neurological dysfunction through correspondence between NIHSS items and CTP. Methods: We included 169 patients with ELVO presenting to Mayo Clinic Rochester or Jacksonville, who had baseline CTP and itemised NIHSS data. Perfusion was quantified as mean transit time using e-CTP (Brainomix Ltd., Oxford, UK) and thresholded to ≥5 s for lesion masking. Voxel-wise lesion-symptom mapping (VLSM) was performed using sparse canonical correlations analysis (Lesymap package, R). Results: Total NIHSS was most strongly predicted by left MCA territory hypoperfusion, corresponding to language-eloquent cortical areas and dominant hemisphere motor tracts (figure 1). Contralateral limb motor deficits (NIHSS 5 and 6) were mainly associated with subcortical and white matter hypoperfusion; there was an additional strong signal for left frontal cortex in language function (NIHSS 9). The remaining NIHSS items were less well localised. Conclusions: Expanding on previous pilot data, our results provide further evidence for the feasibility of hypoperfusion-to-symptom mapping in ELVO. This could allow for more nuanced clinical-imaging mismatch determination, and selection of patients based on specific neurological deficits that may be reversible.

Associations Between Brain Volumes and Cognitive Tests with Hypertensive Burden in UK Biobank.

Background:Mid-life hypertension is an established risk factor for cognitive impairment and dementia and related to greater brain atrophy and poorer cognitive performance. Previous studies often have small sample sizes from older populations that lack utilizing multiple measures to define hypertension such as blood pressure, self-report information, and medication use; furthermore, the impact of the duration of hypertension is less extensively studied.Objective:To investigate the relationship between hypertension defined using multiple measures and length of hypertension with brain measure and cognition.Methods:Using participants from the UK Biobank MRI visit with blood pressure measurements (n = 31,513), we examined the cross-sectional relationships between hypertension and duration of hypertension with brain volumes and cognitive tests using generalized linear models adjusted for confounding.Results:Compared with normotensives, hypertensive participants had smaller brain volumes, larger white matter hyperintensities (WMH), and poorer performance on cognitive tests. For total brain, total grey, and hippocampal volumes, those with greatest duration of hypertension had the smallest brain volumes and the largest WMH, ventricular cerebrospinal fluid volumes. For other subcortical and white matter microstructural regions, there was no clear relationship. There were no significant associations between duration of hypertension and cognitive tests.Conclusion:Our results show hypertension is associated with poorer brain and cognitive health however, the impact of duration since diagnosis warrants further investigation. This work adds further insights by using multiple measures defining hypertension and analysis on duration of hypertension which is a substantial advance on prior analyses—particularly those in UK Biobank which present otherwise similar analyses on smaller subsets.

Brain morphometry and diminished physical growth in Bangladeshi children growing up in extreme poverty: A longitudinal study

Diminished physical growth is a common marker of malnutrition and it affects approximately 200 million children worldwide. Despite its importance and prevalence, it is not clear whether diminished growth relates to brain development and general cognitive ability. Further, diminished growth is more common in areas of extreme poverty, raising the possibility that it may mediate previously shown links between socioeconomic status (SES) and brain structure. To address these gaps, 79 children growing up in an extremely poor, urban area of Bangladesh underwent MRI at age six years. Structural brain images were submitted to Mindboggle software, a Docker-compliant and high-reproducibility tool for tissue segmentation and regional estimations of volume, surface area, cortical thickness, sulcal depth, and mean curvature. Diminished growth predicted brain morphometry and mediated the link between SES and brain morphometry most consistently for subcortical and white matter subcortical volumes. Meanwhile, brain volume in left pallidum and right ventral diencephalon mediated the relationship between diminished growth and full-scale IQ. These findings offer malnutrition as one possible pathway through which SES affects brain development and general cognitive ability in areas of extreme poverty.