Percentage Of Total Intracranial Volume Research Articles

Abstract TP41: Racial Differences in Cumulative Blood Pressure Exposure and Hippocampal Subvolumes

Introduction: We previously showed that a higher cumulative systolic blood pressure (cSBP) burden from young adulthood to midlife was associated with lower hippocampal volumes in Black but not White individuals independent of other vascular risk factors (VRF). And this difference was particularly evident in those with highest cSBP. In this study, we further explored these relationships by examining the impact of cSBP exposure on different hippocampal subvolumes. Methods: Thirty-four participants (18 black, 16 white) in the highest quartile of cSBP and longitudinal VRF exposure over 30 years with available brain MRI at the year 30 visit of the Coronary Artery Risk Development in Young Adults (CARDIA) cohort were used for this analysis. We measured the hippocampal subvolumes (CA1, CA2/3, and CA4) standardized as a percentage of total intracranial volume. T1 MRI images were processed using FreeSurfer (7.3.2) recon-all and the hippocampal sub-regions were segmented based on the computational atlas available in FreeSurfer. Results: Among the three regions, cSBP was only associated with CA1 subvolume in Black but not White participants. Racial differences were most evident in the CA1 hippocampal subvolume (p=0.099) and this difference remained even when other VRF were accounted for. Conclusion: Blacks with higher cSBP exposure over young adulthood to midlife, have smaller hippocampal CA1 subvolumes, which parallels the disparities in cSBP we previously reported. Our findings further highlight the anatomic vulnerability of the CA1 region to cSBP exposure and underscore the importance of early blood pressure control, particularly in minority populations where early screening for VRF may be limited.

Inflammatory and synaptic PET imaging in behavioural variant frontotemporal dementia caused by a repeat expansion in C9orf72 (C9orf72‐FTD)

AbstractBackgroundPathophysiological mechanisms associated with neurodegeneration include chronic neuroinflammation and synaptic dysfunction/loss. Radiotracer [11C]PBR28 is a marker of inflammation which binds to a translocator protein expressed by activated microglia. [11C]UCB‐J is a marker of synaptic density which binds to synaptic vesicle protein 2A. We evaluated both tracers as biomarkers of C9orf72‐FTD.MethodThree individuals with C9orf72‐FTD (mean age 62.7 years) underwent two PET scans between 3 and 13 months apart using [11C]PBR28 and [11C]UCB‐J. Dynamic PET data were acquired for 90 minutes following injection of each tracer. Arterial plasma input functions were generated from arterial blood samples. Participants also had volumetric MRI scans for each PET scan. Age‐matched controls from different cohorts underwent the same procedures (n = 5 for [11C]PBR28; n = 17 for [11C]UCB‐J).Regions of interest (ROIs) were defined on co‐registered T1‐weighted MR images using the CIC anatomical atlas. [11C]PBR28 BPND values were generated using a simplified reference tissue model with a cerebellar reference region. [11C]UCB‐J DVR‐1 values were generated using regional VT normalised to the VT in the centrum semiovale. ROI volumes were expressed as a percentage of total intracranial volume. W‐scores computed from each control cohort, using age and gender as covariates, illustrated the magnitude of differences between cases and controls. W‐scores >1.65 were considered abnormal for [11C]PBR28 and ←1.65 for [11C]UCB‐J and MRI.Result[11C]PBR28 w‐scores indicated significant neuroinflammation in FTD but varied between cases. Differences in BPND were greater than in volume in frontal/temporal/cingulate cortices in the individual with the longest disease duration (DD) (16‐17 years). Inversely, in the individual with the shortest DD (1‐2 years), there were greater differences in volume than BPND in most ROIs.[11C]UCB‐J w‐scores indicated significant synaptic dysfunction/loss and were lower than w‐scores of volume in all cortical ROIs. In the individual with the longest DD, differences in [11C]PBR28 were greater than in [11C]UCB‐J in most ROIs. An inverse pattern again observed in the individual with the shortest DD suggests synaptic dysfunction/loss may precede significant neuroinflammation.ConclusionInflammatory and synaptic PET may provide more sensitive biomarkers of C9orf72‐FTD than MRI. Variability in PET signal within this genotype may be explained by DD.

Relationship between white matter lesion coalescence and plasma cystatin C in an ethnically diverse population

AbstractBackgroundBrain and kidney share anatomical similarities in terms of the small vessels serving their irrigation. Previous work have shown associations between markers of cerebral small vessel disease (CSVD) e.g. white matter hyperintensities (WMH) and markers of renal function e.g. cystatin C. Few studies have however investigated the relationship between renal function and more detailed descriptions of lesion shape and distributionMethod768 individuals from the tri‐ethnic SABRE cohort underwent brain MRI including T1w and FLAIR sequences. WMH were automatically segmented and an overall measure of coalescence was derived from the lesion map ranging from 0 (only punctuate lesions) to 4 (high level of coalescence). Regional coalescence measures according to distance from the ventricles were further derived in 4 equidistant layers. Clinic blood samples were available for 731 individuals (45% female, mean age 71.3 (SD 6.4) years) including from 311 European; 172 African Caribbean; and 248 South Asian ethnicity. Blood measures include plasma cystatin C, a marker of glomerular filtration rate, white blood cell count (WBC) and HbA1c. Associations between cystatin C and coalescence score or lesion volume expressed as percentage of total intracranial volume were investigated using robust linear regression adjusting for age, ethnicity, sex, HbA1c and WBC; all factors known to be associated with cystatin C levels and WMH.ResultCystatin C was positively associated with male sex, WBC and HbA1c, and differed across ethnicities being highest in South Asians and lowest in African Caribbeans. After adjusting for potential confounders, cystatin C was positively associated with overall coalescence score (b = 0.026 [0.004;0.047], p = 0.018) despite unconvincing evidence of an association with overall lesion volume (b = 0.003 [‐0.0003; 0.007], p = 0.066). Associations between cystatin C and coalescence score were stronger in the South Asian group (b = 0.066 [0.027;0.105], p interaction = 0.001). Associations between cystatin C and coalescence score were similar across different layers.ConclusionShape patterns of WMH, rather than overall WMH volume, may provide a more sensitive measure to assess the relationship with markers of small vessel disease in the kidneys.

Relationship between white matter lesion coalescence and plasma cystatin C in an ethnically diverse population.

AbstractBackground: Brain and kidney share anatomical similarities in terms of the small vessels serving their irrigation. Previous work have shown associations between markers of cerebral small vessel disease (CSVD) e.g. white matter hyperintensities (WMH) and markers of renal function e.g. cystatin C. Few studies have however investigated the relationship between renal function and more detailed descriptions of lesion shape and distributionMethod768 individuals from the tri‐ethnic SABRE cohort underwent brain MRI including T1w and FLAIR sequences. WMH were automatically segmented and an overall measure of coalescence was derived from the lesion map ranging from 0 (only punctuate lesions) to 4 (high level of coalescence). Regional coalescence measures according to distance from the ventricles were further derived in 4 equidistant layers. Clinic blood samples were available for 731 individuals (45% female, mean age 71.3 (SD 6.4) years) including from 311 European; 172 African Caribbean; and 248 South Asian ethnicity. Blood measures include plasma cystatin C, a marker of glomerular filtration rate, white blood cell count (WBC) and HbA1c. Associations between cystatin C and coalescence score or lesion volume expressed as percentage of total intracranial volume were investigated using robust linear regression adjusting for age, ethnicity, sex, HbA1c and WBC; all factors known to be associated with cystatin C levels and WMH.ResultCystatin C was positively associated with male sex, WBC and HbA1c, and differed across ethnicities being highest in South Asians and lowest in African Caribbeans. After adjusting for potential confounders, cystatin C was positively associated with overall coalescence score (b = 0.026 [0.004;0.047], p = 0.018) despite unconvincing evidence of an association with overall lesion volume (b = 0.003 [‐0.0003; 0.007], p = 0.066). Associations between cystatin C and coalescence score were stronger in the South Asian group (b = 0.066 [0.027;0.105], p interaction = 0.001). Associations between cystatin C and coalescence score were similar across different layers.ConclusionShape patterns of WMH, rather than overall WMH volume, may provide a more sensitive measure to assess the relationship with markers of small vessel disease in the kidneys.

Three-Dimensional Assessment of Frontal Bossing and Temporal Pinching in Patients with Sagittal Craniosynostosis Using Curvature Analysis.

Sagittal craniosynostosis results in varying degrees of frontal bossing and bilateral temporal pinching. This study assessed the three-dimensional changes in these regions using curvature analysis and volumetric analysis before and 1 year after extended sagittal strip craniectomy (ESC) with postoperative helmet therapy. A retrospective review of three-dimensional photographs of 50 subjects treated with ESC with postoperative helmet therapy and 50 age-matched controls was performed. Images were collected preoperatively and 1 year postoperatively. Forehead convexity and temple concavity were quantified. Computed tomographic scans of subjects with and without sagittal synostosis were analyzed to assess the percentage of total intracranial volume (ICV) in the anterior cranial fossa before and after ESC with postoperative helmet therapy. Forehead convexity in the ESC with postoperative helmet therapy group preoperatively (24.49 ± 3.16 m -1 ) was significantly greater than controls (22.48 ± 3.84 m -1 ; P = 0.005). Forehead convexity significantly decreased after ESC with postoperative helmet therapy (18.79 ± 2.43 m -1 ; P < 0.001) and did not differ from controls (19.67 ± 3.08 m -1 ; P = 0.115). The ESC group had more concave temples preoperatively (-10.27 ± 4.37 m -1 ) as compared with controls (-6.99 ± 3.55 m -1 ; P < 0.001). Temple concavity significantly decreased after ESC (-4.82 ± 3.17 m -1 ; P < 0.001) and did not differ from controls (-5.64 ± 3.27 m -1 ; P = 0.075). In the ESC group, the percentage ICV in the anterior cranial fossa decreased from 22.03% to 18.99% after surgery, whereas the anterior volume in controls was stable (17.74% to 16.81%). The ESC group had significantly greater forehead convexity, temple concavity and anterior cranial fossa volume compared with controls. One year after ESC with postoperative helmet therapy, forehead convexity, temple concavity, and percentage ICV in the anterior fossa were comparable to controls. Therapeutic, IV.

Association of Blood Cell Parameters of Peripheral Inflammation With Brain Imaging Measures

Neutrophil to lymphocyte ratio (NLR), red cell distribution width (RDW), and mean platelet volume (MPV), are easily measured circulating blood cell parameters that reflect chronic peripheral inflammation which increases risk for dementia and Alzheimer’s disease (AD). We investigated the cross-sectional association between these blood cell parameters and brain MRI measures, including total cerebral brain volume (TCBV) as percentage of total intracranial volume (TCV) to correct for differences in head size, hippocampal volume (HPV) and log transformed white matter hyperintensity (WMH) volume, in the Framingham Heart Study (FHS) cohorts. We identified 2882 FHS participants 25 to 92 years of age (mean 59 years), 53% women, who attended an exam that included a complete blood cell count sample and received a brain MRI within five years of blood draw. We used linear mixed effect models to examine associations, adjusting for age, age^2, sex, education, cohort, time between blood draw and MRI, prevalent cardiovascular disease, C-reactive protein, APOE-ϵ4 genotype and TCV for HPV and WMH, and accounting for familial correlation using a random effect. We observed significant (p≤0.01) associations between higher RDW and smaller TCBV, and between elevated NLR and larger WMH volume. Analysis on an older subgroup (age ≥60 years, mean 71 years, n=1357) demonstrated larger effect sizes and additional significance between increased RDW with smaller HPV. We conclude that chronic peripheral inflammation as measured by NLR and RDW associates with MRI measures of brain aging (TCBV, HPV) and vascular brain injury (WMH) in FHS, with stronger impact in participants ≥60 years.

Synaptic PET imaging using [11C]UCB‐J in frontotemporal dementia

AbstractBackgroundA number of pathophysiological mechanisms are associated with neurodegeneration, including synaptic dysfunction and/or loss. Novel radiotracers which enable the quantification of synaptic proteins in vivo have not previously been explored in frontotemporal dementia (FTD). We used [11C]UCB‐J PET to measure the density of synaptic vesicle protein 2A (SV2A) in FTD.MethodSix participants with behavioural variant FTD (mean age 61.8, SD 5.4) and 17 cognitively normal participants (63.7, 12.5) underwent 90‐minute dynamic acquisition PET scans following injection of [11C]UCB‐J, with metabolite corrected arterial input function. Thirteen regions of interest (ROIs) were defined on individual MR images using the CIC anatomical atlas. Regional density was evaluated using the regional VT normalised to the VT in the centrum semiovale (DVR‐1). Groups were compared using Mann‐Whitney tests with Bonferroni correction for multiple comparisons. W‐scores were computed from the 17 controls, with age and gender as covariates, to compare the magnitude of group differences in regional volumes versus [11C]UCB‐J distribution. Volumes were expressed as a percentage of total intracranial volume. A w‐score of &lt;‐1.65 was considered abnormal.ResultWe found significant reductions in regional density of SV2A in FTD compared to controls in multiple cortical and subcortical regions: frontal, temporal, parietal, insula, anterior cingulate and posterior cingulate cortices (all 0.001), as well as the hippocampus, amygdala, thalamus and cerebellum (all 0.001). The w‐score analysis revealed significant reductions in SV2A density in FTD in all 13 ROIs, with the greatest reduction in the anterior cingulate (‐4.2), and in volume in 8 ROIs, with the greatest reduction in the temporal lobe (‐6.4). The magnitude of SV2A density loss was greater than the magnitude of volume loss in most ROIs (9/13), and there was more variability in the reduction in volume than there was in SV2A density (SD range [11C]UCB‐J 0.7‐2.1, volume 1.4‐3.9).ConclusionSignificant reductions in [11C]UCB‐J distribution indicate reduced synaptic density in disease‐relevant regions in FTD, which surpass reductions in volume. This suggests that [11C]UCB‐J PET imaging could be a sensitive biomarker of synaptic dysfunction in FTD, with future studies focused on its relationship with symptoms and whether it becomes abnormal before symptom onset.

Decreased Basal Ganglia Volume in Cerebral Amyloid Angiopathy.

Background and PurposeCerebral amyloid angiopathy (CAA) is a common pathology of the leptomeningeal and cortical small vessels associated with hemorrhagic and non-hemorrhagic brain injury. Given previous evidence for CAA-related loss of cortical thickness and white matter volume, we hypothesized that CAA might also cause tissue loss in the basal ganglia. MethodsWe compared basal ganglia volumes expressed as a percentage of total intracranial volume (pBGV) of non-demented patients with sporadic and hereditary CAA to age-matched healthy control (HC) and Alzheimer’s disease (AD) cohorts. ResultsPatients with sporadic CAA had lower pBGV (n=80, 1.16%±0.14%) compared to HC (n=80, 1.30%±0.13%, P<0.0001) and AD patients (n=80, 1.23%±0.11%, P=0.001). Similarly, patients with hereditary CAA demonstrated lower pBGV (n=25, 1.26%±0.17%) compared to their matched HC (n=25, 1.36%±0.15%, P=0.036). Using a measurement of normalized basal ganglia width developed for analysis of clinical-grade magnetic resonance images, we found smaller basal ganglia width in patients with CAA-related lobar intracerebral hemorrhage (ICH; n=93, 12.35±1.47) compared to age-matched patients with hypertension-related deep ICH (n=93, 13.46±1.51, P<0.0001) or HC (n=93, 15.45±1.22, P<0.0001). Within the sporadic CAA research cohort, decreased basal ganglia volume was independently correlated with greater cortical gray matter atrophy (r=0.45, P<0.0001), increased basal ganglia fractional anisotropy (r=–0.36, P=0.001), and worse performance on language processing (r=0.35, P=0.003), but not with cognitive tests of executive function or processing speed. ConclusionsThese findings suggest an independent effect of CAA on basal ganglia tissue loss, indicating a novel mechanism for CAA-related brain injury and neurologic dysfunction.

Abstract P64: Longitudinal Brain Structural Changes After Stroke

Background: Stroke causes focal and diffuse structural brain changes that may contribute to subsequent cognitive decline and dementia. We hypothesize that MRI structural measures can detect continued cerebral degeneration over the first year after stroke. We identify predictors for progression of brain atrophy, leukoaraiosis and diffusion tensor imaging (DTI) metrics. Methods: Patients with ischemic stroke were enrolled prospectively in an observational study that included serial brain MRI. Patients underwent MRI FLAIR and DTI at the time of acute stroke and were followed for at least 9 months with multiple MRIs between 30 days and 15 months post-stroke. We used FLAIR to measure brain atrophy as the percent brain parenchymal fraction (BPF) of the total intracranial volume (TICV) and white matter hyperintensity volume (WMHV) as a percentage of TICV. DTI was used to calculate Peak Skeletonized Mean Diffusivity (PSMD), a global measure of white matter integrity previously validated in cerebral small vessel disease. Longitudinal changes in BPF, WMHV or PSMD were measured from 30 days post-stroke onward using linear regression models that included age, stroke volume, baseline BPF and WMHV as predictors. Results: Twenty-six patients had a median of 4 follow-ups over 9-15 months. Median age was 74 years (range 51-84) and 38% were women. Mean stroke volume was 4.5cc (0 - 30cc). Mean BPF was 78% (72 - 86%) and mean baseline WMHV was 1.1% (0.1 - 3.9%). BPF was associated with age and declined by 0.7% per year (t(111) = 2.7, p = 0.007). Progression was associated with baseline BPF (t(111) = -3.4, p &lt; 0.001). WMHV in the non-stroke hemisphere was associated with age and increased by 0.10% per year (t(87) = -5.8, p &lt; 0.001). Accumulation was associated with age (t(87) = 5.8, p &lt; 0.001). PSMD was associated with baseline WMHV and had a relative increase of 1.9% per year in the non-stroke hemisphere and 4.5% in the stroke hemisphere (t(174) = -2.1, p = 0.03). Progression was associated with age (t(174) = 2.3, p = 0.03) and stroke volume (t(174) = 2.4, p = 0.02). Conclusions: During the months after ischemic stroke, BPF, WMHV and PSMD can detect persistent structural changes that may reflect later phases of stroke injury or ongoing contributions of aging, silent ischemia, or neurodegeneration.

Increased self‐reported sleepiness is associated with larger brain volume and less ischemic brain injury in a community sample

AbstractBackgroundSleepiness has been associated with an increased risk of Alzheimer’s disease (AD) and vascular dementia, but few studies have investigated its association with markers of accelerated brain aging. We evaluated the association between sleepiness and MRI measures; and whether the apolipoprotein E4 (APOE4) allele status moderates this relationship.MethodWe studied 492 participants (58.8 ± 8.8 years, 49.4%M) in the Framingham Heart Study aged &gt;40 years without significant neurological diseases, such as dementia and stroke. We used the Epworth Sleepiness Scale (ESS) to assess sleepiness. Brain MRI metrics were volumes of white matter hyperintensities (WMH), total brain, cortical gray matter (GM) and subcortical GM, all investigated as a percentage of total intracranial volume; we also identified covert brain infarcts (CBI). Linear and logistic regressions were used to assess the association between ESS scores and brain structure. Model 1 adjusted for age, age squared, sex, and time between the ESS and MRI (3.3 ± 1.0 years). Model 2 additionally adjusted for APOE4 allele carrier status, Framingham Stroke Risk Profile scores, sleep medication, body mass index, and depression. We included an interaction term between APOE4 allele status and ESS score, adjusted for model 1 covariates, to evaluate potential effect modification.ResultHigher ESS scores, indicating greater sleepiness, were associated with higher total brain volume (b = 0.33; SE = 0.13; p = 0.02), higher cortical GM volume (b = 0.26; SE = 0.12; p = 0.03), and a lower risk of CBI (OR = 0.57; 95%CI = 0.36‐0.93; p = 0.02) adjusted for both models 1 and 2 covariates. These associations were present when further adjusting for the apnea‐hypopnea index, education and habitual sleep duration. A significant interaction was observed between APOE4 and ESS scores (p = 0.008), where higher ESS was associated with higher cortical GM in non‐carriers (b = 0.43; SE = 0.14; p = 0.002). Conversely, in carriers, higher ESS was associated with lower cortical GM (b = ‐0.36; SE = 0.22; p = 0.09, trend).ConclusionIncreased self‐reported sleepiness was associated with findings of better brain health, including higher cortical GM volume and less CBI. Genetic susceptibility to AD modified this relationship, where increased sleepiness was associated with higher cortical GM volume only in APOE4 non‐carriers. Better brain health may be associated with higher self‐reported sleepiness via better cognition and self‐awareness in those who are not at increased risk of developing AD.

Plasma YKL40 as a biomarker for brain aging and injury in three community cohorts

AbstractBackgroundYKL40 is expressed in reactive astrocytes and microglia and is upregulated in numerous neurological conditions associated with heightened neuroinflammation. We explored the utility of circulating YKL40 as a biomarker of accelerated brain aging and subclinical brain injury.MethodYKL40 was measured using the Mesoscale Discovery (MSD) multi‐array assay system from stored plasma in three community‐based cohorts: the Atherosclerosis Risk in the Communities Study (ARIC), the Coronary Artery Risk Development in Young Adults (CARDIA), and the Framingham Heart Study (FHS). MRI‐derived outcomes of total brain volume, hippocampal volume, and white matter hyperintensity volume (WMHV) were expressed as a percentage of total intracranial volume. We derived a general cognitive factor from multiple neuropsychological tests capturing multiple domains using cohort‐specific principal component analysis with a forced single factor solution. We examined the association between log‐transformed and standardized YKL40 levels and MRI and cognitive phenotypes separately in each cohort using linear regression. Cohort specific results were then pooled in random‐effects meta‐analysis. Analyses were cross‐sectional and adjusted for age, age squared, sex, education (for cognition), and the time interval between the blood draw for YKL40 and outcome assessment. A second model included additional adjustments for vascular risk factors and presence of the APOE ε4 allele.ResultAcross cohorts, there were 2782 dementia‐free participants (mean age, 64 years; 45% male; Mean(SD) YKL40 levels = 50689(7114)pg/mL; YKL40 Coefficient of Variation = 7.5%). In random‐effects meta‐analysis, higher YKL40 levels were associated with smaller total brain volume (β±SE, ‐0.24±0.05 per percentage change in brain volume, p&lt;0.0001) and poorer cognitive function (β±SE, ‐0.04±0.02 per unit change in cognitive composite, p=0.03). The association between YKL40 levels and total brain volume remained significant following full multivariable adjustments (β±SE, ‐0.23±0.05 p&lt;0.0001) whereas the association between YKL40 and cognition was attenuated (β±SE, ‐0.04±0.02, p=0.06). YKL40 levels were not associated with hippocampal volume or WMHV (P&gt;0.05).ConclusionHigher plasma YKL40 levels were associated with MRI and cognitive markers of accelerated brain aging, suggesting involvement of astrocytic or microglial mediated neuroinflammation in subclinical brain atrophy and cognitive impairment.

PSMD, a novel marker of small vessel disease, and its association with cognitive function in the community

AbstractBackgroundPeak width of skeletonized mean diffusivity (PSMD) has been proposed as a novel neuroimaging marker for small vessel disease (SVD), which contributes to vascular cognitive impairment and dementia. Although this marker has been related to lower cognitive function in clinical samples with inherited and sporadic SVD, additional research is needed to assess its utility for risk prediction in large, well‐characterized population‐based cohorts.MethodsWe included 929 stroke‐ and dementia‐free participants from the Offspring cohort of the Framingham Heart Study. PSMD was derived from DTI using an automated algorithm, and further log‐transformed to normalize its distribution. To evaluate general cognitive function, we created a composite cognitive score including Logical Memory – immediate and delayed recall, Digit Span Forward and Backward, Category Fluency – animals, Phonemic Fluency – FAS, Trail Making Test A and Test B, and the Boston Naming Test. We used linear regression models to relate PSMD to general cognitive function adjusting for age, sex and educational level. In a secondary model, we additionally adjusted for diabetes, smoking and hypertension. Finally, we included white matter hyperintensity (WMH) volume as percentage of total intracranial volume in the primary and secondary models to assess the contribution of PSMD beyond WMH.ResultsHigher PSMD values were associated with lower general cognitive function (Beta (SE), ‐0.61 (0.10), p&lt;0.001). Results remained virtually unchanged after additional adjustment for vascular risk factors in the secondary model (‐0.60 (0.10), p&lt;0.001). After the inclusion of WMH, associations remained significant in the primary (‐0.58 (0.11), p&lt;0.001) and secondary (‐0.57 (0.11), p&lt;0.001) models, with PSMD explaining an additional 2% of the variance in cognition beyond WMH.ConclusionPSMD was strongly associated with general cognitive function in our sample, suggesting that this novel marker may be suitable for risk prediction for SVD in community‐based samples, and is potentially a better predictor than well‐established markers such as WMH. Additional validation and longitudinal analyses are currently underway in population‐based cohorts and clinical samples in the context of the MarkVCID consortium.

A Method to Estimate Brain Volume from Head CT Images and Application to Detect Brain Atrophy in Alzheimer Disease.

Total brain volume and total intracranial volume are important measures for assessing whole-brain atrophy in Alzheimer disease, dementia, and other neurodegenerative diseases. Unlike MR imaging, which has a number of well-validated fully-automated methods, only a handful of methods segment CT images. Available methods either use enhanced CT, do not estimate both volumes, or require formal validation. Reliable computation of total brain volume and total intracranial volume from CT is needed because head CTs are more widely used than head MRIs in the clinical setting. We present an automated head CT segmentation method (CTseg) to estimate total brain volume and total intracranial volume. CTseg adapts a widely used brain MR imaging segmentation method from the Statistical Parametric Mapping toolbox using a CT-based template for initial registration. CTseg was tested and validated using head CT images from a clinical archive. CTseg showed excellent agreement with 20 manually segmented head CTs. The intraclass correlation was 0.97 (P < .001) for total intracranial volume and 0.94 (P < .001) for total brain volume. When CTseg was applied to a cross-sectional Alzheimer disease dataset (58 with Alzheimer disease patients and 58 matched controls), CTseg detected a loss in percentage total brain volume (as a percentage of total intracranial volume) with age (P < .001) as well as a group difference between patients with Alzheimer disease and controls (P < .01). We observed similar results when total brain volume was modeled with total intracranial volume as a confounding variable. In current clinical practice, brain atrophy is assessed by inaccurate and subjective "eyeballing" of CT images. Manual segmentation of head CT images is prohibitively arduous and time-consuming. CTseg can potentially help clinicians to automatically measure total brain volume and detect and track atrophy in neurodegenerative diseases. In addition, CTseg can be applied to large clinical archives for a variety of research studies.

Reduced left amygdala volume in patients with dissociative seizures (psychogenic nonepileptic seizures)

PurposeThis study specifically investigated differences of amygdalar and hippocampal volumes between patients with dissociative seizures (DS), mesial temporal lobe sclerosis (MTS), and normal controls (NC). MethodsBetween 2003 and 2018, 127 patients diagnosed with DS and 278 with MTS were recruited. An additional 52 NC subjects were recruited between 2015 and 2018. We retrospectively selected 29 patients with DS (male:female, 6:23) with absence of structural confounding factors and obtained sex- and age-matched MTS and NC. We used Neuroreader to assess the volume of the amygdala and hippocampus as a percentage of total intracranial volume based on thin-slice (0.9–1.2 mm) T1-weighted images. Statistical analyses controlled for psychiatric comorbidity and logistic regression were used to evaluate efficacy of these values for individual-level diagnosis. ResultsThe left amygdala and right hippocampus were significantly smaller in DS compared to NC (both p = 0.04), which was not explained by differences in psychiatric comorbidity. When controlling for ipsilateral hippocampal or amygdala volume, which was seen equally in all groups (Spearman, p < 0.02), these differences were no longer significant (amygdala, p = 0.16, hippocampus, p = 0.18), suggesting that amygdalar and hippocampal atrophy may reflect network or regional changes rather than focal abnormalities. The three-way accuracy for differentiating DS, MTS, and NC using these data was 64 % (95 % confidence interval: 54–74 %). ConclusionVolumetric analysis demonstrates smaller left amygdalar and right hippocampal volumes in patients with DS compared to NC, which may mirror abnormalities in functional networks seen in conversion disorders and post-traumatic stress disorder.

Improved Detection of Subtle Mesial Temporal Sclerosis: Validation of a Commercially Available Software for Automated Segmentation of Hippocampal Volume.

Identification of mesial temporal sclerosis is critical in the evaluation of individuals with temporal lobe epilepsy. Our aim was to assess the performance of FDA-approved software measures of hippocampal volume to identify mesial temporal sclerosis in patients with medically refractory temporal lobe epilepsy compared with the initial clinical interpretation of a neuroradiologist. Preoperative MRIs of 75 consecutive patients who underwent a temporal resection for temporal lobe epilepsy from 2011 to 2016 were retrospectively reviewed, and 71 were analyzed using Neuroreader, a commercially available automated segmentation and volumetric analysis package. Volume measures, including hippocampal volume as a percentage of total intracranial volume and the Neuroreader Index, were calculated. Radiologic interpretations of the MR imaging and pathology from subsequent resections were classified as either mesial temporal sclerosis or other, including normal findings. These measures of hippocampal volume were evaluated by receiver operating characteristic curves on the basis of pathologic confirmation of mesial temporal sclerosis in the resected temporal lobe. Sensitivity and specificity were calculated for each method and compared by means of the McNemar test using the optimal threshold as determined by the Youden J point. Optimized thresholds of hippocampal percentage of a structural volume relative to total intracranial volume (<0.19%) and the Neuroreader Index (≤-3.8) were selected to optimize sensitivity and specificity (89%/71% and 89%/78%, respectively) for the identification of mesial temporal sclerosis in temporal lobe epilepsy compared with the initial clinical interpretation of the neuroradiologist (50% and 87%). Automated measures of hippocampal volume predicted mesial temporal sclerosis more accurately than radiologic interpretation (McNemar test, P < .0001). Commercially available automated segmentation and volume analysis of the hippocampus accurately identifies mesial temporal sclerosis and performs significantly better than the interpretation of the radiologist.

Are Anesthesia and Surgery during Infancy Associated with Decreased White Matter Integrity and Volume during Childhood?

Anesthetics have neurotoxic effects in neonatal animals. Relevant human evidence is limited. We sought such evidence in a structural neuroimaging study. Two groups of children underwent structural magnetic resonance imaging: patients who, during infancy, had one of four operations commonly performed in otherwise healthy children and comparable, nonexposed control subjects. Total and regional brain tissue composition and volume, as well as regional indicators of white matter integrity (fractional anisotropy and mean diffusivity), were analyzed. Analyses included 17 patients, without potential confounding central nervous system problems or risk factors, who had general anesthesia and surgery during infancy and 17 control subjects (age ranges, 12.3 to 15.2 yr and 12.6 to 15.1 yr, respectively). Whole brain white matter volume, as a percentage of total intracranial volume, was lower for the exposed than the nonexposed group, 37.3 ± 0.4% and 38.9 ± 0.4% (least squares mean ± SE), respectively, a difference of 1.5 percentage points (95% CI, 0.3 to 2.8; P = 0.016). Corresponding decreases were statistically significant for parietal and occipital lobes, infratentorium, and brainstem separately. White matter integrity was lower for the exposed than the nonexposed group in superior cerebellar peduncle, cerebral peduncle, external capsule, cingulum (cingulate gyrus), and fornix (cres) and/or stria terminalis. The groups did not differ in total intracranial, gray matter, and cerebrospinal fluid volumes. Children who had anesthesia and surgery during infancy showed broadly distributed, decreased white matter integrity and volume. Although the findings may be related to anesthesia and surgery during infancy, other explanations are possible.

Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis

Frontotemporal dementia is a highly heritable neurodegenerative disorder. In about a third of patients, the disease is caused by autosomal dominant genetic mutations usually in one of three genes: progranulin (GRN), microtubule-associated protein tau (MAPT), or chromosome 9 open reading frame 72 (C9orf72). Findings from studies of other genetic dementias have shown neuroimaging and cognitive changes before symptoms onset, and we aimed to identify whether such changes could be shown in frontotemporal dementia. We recruited participants to this multicentre study who either were known carriers of a pathogenic mutation in GRN, MAPT, or C9orf72, or were at risk of carrying a mutation because a first-degree relative was a known symptomatic carrier. We calculated time to expected onset as the difference between age at assessment and mean age at onset within the family. Participants underwent a standardised clinical assessment and neuropsychological battery. We did MRI and generated cortical and subcortical volumes using a parcellation of the volumetric T1-weighted scan. We used linear mixed-effects models to examine whether the association of neuropsychology and imaging measures with time to expected onset of symptoms differed between mutation carriers and non-carriers. Between Jan 30, 2012, and Sept 15, 2013, we recruited participants from 11 research sites in the UK, Italy, the Netherlands, Sweden, and Canada. We analysed data from 220 participants: 118 mutation carriers (40 symptomatic and 78 asymptomatic) and 102 non-carriers. For neuropsychology measures, we noted the earliest significant differences between mutation carriers and non-carriers 5 years before expected onset, when differences were significant for all measures except for tests of immediate recall and verbal fluency. We noted the largest Z score differences between carriers and non-carriers 5 years before expected onset in tests of naming (Boston Naming Test -0·7; SE 0·3) and executive function (Trail Making Test Part B, Digit Span backwards, and Digit Symbol Task, all -0·5, SE 0·2). For imaging measures, we noted differences earliest for the insula (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume was 0·80% in mutation carriers and 0·84% in non-carriers; difference -0·04, SE 0·02) followed by the temporal lobe (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume 8·1% in mutation carriers and 8·3% in non-carriers; difference -0·2, SE 0·1). Structural imaging and cognitive changes can be identified 5-10 years before expected onset of symptoms in asymptomatic adults at risk of genetic frontotemporal dementia. These findings could help to define biomarkers that can stage presymptomatic disease and track disease progression, which will be important for future therapeutic trials. Centres of Excellence in Neurodegeneration.

The pimple sign of progressive supranuclear palsy syndrome

BackgroundSome patients with progressive supranuclear palsy syndrome (PSPS) demonstrate a focal area of midbrain hypometabolism on FDG-PET scans which we call the ‘pimple sign’. We assessed its association with midbrain atrophy, its reliability and its ability to differentiate PSPS from corticobasal syndrome (CBS) and multiple system atrophy (MSA). MethodsWe identified 67 patients with PSPS, CBS or MSA who had volumetric MRI as well as FDG-PET imaging. Midbrain volume was measured and expressed as a percentage of total intracranial volume. Two independent, blinded specialists rated the ‘pimple sign’ on FDG-PET as ‘absent’, ‘possible’ or ‘definite’. Midbrain volumes were compared across these groups and reliability assessed with the kappa statistic. Sensitivity and specificity were calculated using CBS and MSA patients as controls. ResultsMidbrain volume was decreased in the ‘definite’ group compared to the ‘absent’ and ‘possible’ groups (p = 0.0036). Inter-rater reliability for the pimple sign was high (κ = 0.90). A ‘definite pimple sign’ had a high specificity (100%) but low sensitivity (29%) for PSPS, whilst the presence of a possible or definite sign had a sensitivity of 79%. ConclusionThe ‘pimple sign’ of PSPS is associated with midbrain atrophy, and may be helpful in differentiating PSPS from CBS and MSA.

Database of normal japanese gray matter volumes in the default mode network

To show the gray matter volumes in the default mode network (DMN) using the atlas-based method and to evaluate age-related volume change in the DMN region. Estimation of gray matter volumes is interesting research because previous reports showed an association with gray matter volume (GMV) and diseases. We focused on five nodes of the DMN (posterior cingulate, precuneus, lateral temporal cortex [LTC], medial prefrontal cortex, and inferior parietal lobule). In all, 1122 healthy adults were included in the present study. T1-weighted magnetic resonance (MR) images were obtained using a 3T-MR scanner. To investigate GMV in the DMN, segmented gray matter images were measured by the atlas-based method, using Statistical Parametric Mapping 5. Volumes were expressed using three different methods: region of interest (ROI)-volume (mL), the volume itself; ROI-TIV (%), as a percentage of total intracranial volume (individual difference of head size is corrected); and ROI-GMV (%), as a percentage of gray matter volume (individual difference of atrophy speed for aging is corrected). Negative correlations between measurement values on ROI and age were observed in all five ROIs of the DMN region by two measures of volume (ROI-volume (mL) and ROI-TIV (%)), in both genders. In contrast, positive correlations between measurement values on ROI and age were observed in the posterior cingulate and LTC with ROI-GMV (%), in both genders. The present study is the first report about volume change in the DMN that includes age-related effects.

Quantitative Magnetic Resonance Imaging Differences Between Alzheimer Disease With and Without Subcortical Lacunes

Previous reports showed that patients with Alzheimer disease (AD) frequently have coexisting vascular-related pathologies, such as cerebral infarcts and white matter lesions. The aim of this study was to determine the effects of subcortical lacunar infarcts on brain structure in patients with AD. Semi-automated tissue segmentation and volumetry of magnetic resonance imaging data were performed in 38 AD patients without lacunes (AD-L), 24 AD patients with subcortical lacunes (AD+L), and 40 age-matched cognitively healthy subjects without lacunes. The following tissue volumes were quantified, expressed as percentage of total intracranial volume: ventricular cerebrospinal fluid (CSF), sulcal CSF, cortical gray matter (GM), subcortical GM, white matter (WM), white matter signal hyperintensities (WMSH), lacunes, and hippocampus. There was no difference in the Mini-Mental State Examination between the two AD groups. AD+L patients compared with AD-L subjects had significantly greater volumes of WMSH and ventricular CSF spaces (as expected) but smaller sulcal CSF spaces and no significant increase in cortical GM atrophy (both unexpected). In the AD groups, ventricular CSF correlated inversely with cortical GM but not with WM; sulcal CSF correlated inversely with cortical GM and WM. Cognitive impairment was associated with sulcal CSF volume but not with volumes of WMSH or lacunes. In conclusion, the presence of subcortical lacunes in those with AD is associated with more WM lesions and ventriculomegaly but not with cortical atrophy.