Frontal Gray Matter Research Articles

Associative memory is more strongly predicted by age-related differences in the prefrontal cortex than medial temporal lobes

It is well established that episodic memory declines with age and one of the primary explanations for this decline is an age-related impairment in the ability to form new associations. At a neural level, both the medial temporal lobe (MTL) and lateral prefrontal cortex (PFC) are thought to be critical for associative memory, and grey matter volume loss in these regions has been associated with age-related declines in episodic memory. While some recent work has compared the relative contributions of grey matter volume in MTL and PFC regions to item and associative memory, studies investigating the unique and shared contributions of age-related differences in the MTL and PFC to memory differences are still rare. In this study, we use a lifespan approach to examine the relationship between grey matter volume within substructures of the MTL and PFC on the one hand and item and associative memory on the other. To this end, we used data from over 300 healthy individuals uniformly spread across the adult lifespan from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) and tested the multivariate relationship between grey matter volumes and item/associative memory scores using canonical correlation analysis. We show that structures of the PFC alone predict memory performance better than either structures of the MTL alone or PFC and MTL combined. Moreover, our results also indicate that grey matter volume in the inferior frontal gyrus - pars opercularis, superior frontal gyrus, and middle frontal gyrus relates most strongly to memory (particularly associative memory, which loaded higher than item memory) and this effect persists when controlling for age and education. Finally, we also show that the relationship between frontal grey matter volume and memory is not moderated by age or sex. Taken together, these findings emphasize the critical role of the frontal lobes, and the control processes they subserve, in determining the effects of age on associative memory.

A Systematic Review on the Potential Acceleration of Neurocognitive Aging in Older Cancer Survivors.

As survival rates increase, more emphasis has gone to possible cognitive sequelae in older cancer patients, which could be explained by accelerated brain aging. In this review, we provide a complete overview of studies investigating neuroimaging, neurocognitive, and neurodegenerative disorders in older cancer survivors (>65 years), based on three databases (Pubmed, Web of Science and Medline). Ninety-six studies were included. Evidence was found for functional and structural brain changes (frontal regions, basal ganglia, gray and white matter), compared to healthy controls. Cognitive decline was mainly found in memory functioning. Anti-hormonal treatments were repeatedly associated with cognitive decline (tamoxifen) and sometimes with an increased risk of Alzheimer's disease (androgen deprivation therapy). Chemotherapy was inconsistently associated with later development of cognitive changes or dementia. Radiotherapy was not associated with cognition in patients with non-central nervous system cancer but can play a role in patients with central nervous system cancer, while neurosurgery seemed to improve their cognition in the short-term. Individual risk factors included cancer subtypes (e.g., brain cancer, hormone-related cancers), treatment (e.g., anti-hormonal therapy, chemotherapy, cranial radiation), genetic predisposition (e.g., APOE, COMT, BDNF), age, comorbidities (e.g., frailty, cognitive reserve), and psychological (e.g., depression, (post-traumatic) distress, sleep, fatigue) and social factors (e.g., loneliness, limited caregiver support, low SES). More research on accelerated aging is required to guide intervention studies.

Genomic patterns linked to gray matter alterations underlying working memory deficits in adults and adolescents with attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder, with onset in childhood and a considerable likelihood to persist into adulthood. Our previous work has identified that across adults and adolescents with ADHD, gray matter volume (GMV) alteration in the frontal cortex was consistently associated with working memory underperformance, and GMV alteration in the cerebellum was associated with inattention. Recent knowledge regarding ADHD genetic risk loci makes it feasible to investigate genomic factors underlying these persistent GMV alterations, potentially illuminating the pathology of ADHD persistence. Based on this, we applied a sparsity-constrained multivariate data fusion approach, sparse parallel independent component analysis, to GMV variations in the frontal and cerebellum regions and candidate risk single nucleotide polymorphisms (SNPs) data from 341 unrelated adult participants, including 167 individuals with ADHD, 47 unaffected siblings, and 127 healthy controls. We identified one SNP component significantly associated with one GMV component in superior/middle frontal regions and replicated this association in 317 adolescents from ADHD families. The association was stronger in individuals with ADHD than in controls, and stronger in adults and older adolescents than in younger ones. The SNP component highlights 93 SNPs in long non-coding RNAs mainly in chromosome 5 and 21 protein-coding genes that are significantly enriched in human neuron cells. Eighteen identified SNPs have regulation effects on gene expression, transcript expression, isoform percentage, or methylation level in frontal regions. Identified genes highlight MEF2C, CADM2, and CADPS2, which are relevant for modulating neuronal substrates underlying high-level cognition in ADHD, and their causality effects on ADHD persistence await further investigations. Overall, through a multivariate analysis, we have revealed a genomic pattern underpinning the frontal gray matter variation related to working memory deficit in ADHD.

Abstract 123: In Vivo Permeability Of The Aging Brain With Cerebral Microbleeds

Introduction: Age-related cerebral microbleeds (CMBs) are vascular changes associated with an increased risk of intracerebral hemorrhage (ICH) and neurocognitive decline. CMBs share a strikingly similar appearance on MRI to cerebral cavernous malformations (CCMs), which are leaky capillary lesions predisposing patients to brain bleeding. Our team had previously shown increased vascular permeability in CCM and in the brain of older subjects, with common circulating biomarkers of angiogenesis and inflammation. We examine here whether vascular permeability is greater in the aging brain harboring CBMs. Methods: Dynamic Contrast-Enhanced Quantitative Perfusion (DCEQP) MRI, which assesses vascular permeability, was acquired for 7 patients with CMBs (>50 years old), 10 old (>50 years old), and 9 young (18-30 years old) healthy subjects without CMBs. Cases with active brain disease, stroke or seizure in the prior year were excluded. DCEQP scans were co-registered onto their respective T1-weighted images, normalized using the Desikan-Killiany atlas, and finally segmented into white and gray matter within frontal, temporal, parietal, and occipital lobes. The mean permeability was calculated within each segmented area, and values were compared between the 3 groups of interest. Results: Increased permeability was observed within the frontal white and gray matter as well as the parietal gray matter of patients with CMBs compared to age matched old healthy controls (both: p<0.05). In addition, greater background brain permeability was also observed in old healthy controls compared to young healthy controls, in the occipital white matter, as well as the white and gray matter in the temporal and parietal lobes (all: p<0.05). Conclusion: We confirm that the human brain exhibits increased vascular permeability with aging, and this is more pronounced in brains harboring CMBs. This may provide insight into the pathogenesis of CMBs, potentially reflecting end stage age-related failure of the blood brain barrier, associated with frank bleeding. These results offer a starting point for the development of diagnostic and prognostic imaging biomarkers of CMBs, which can help stratify patients at higher risk of future ICH and cognitive decline.

Quantitative morphometric changes in vascular mild cognitive impairment patients: early diagnosis of dementia.

Vascular mild cognitive impairment (VMCI) is an early and reversible stage of dementia. Volume differences in regional gray matter may reveal the development and prognosis of VMCI. This study selected 2 of the most common types of VMCI, namely, periventricular white matter hyperintensities (PWMH, n = 14) and strategic single infarctions (SSI, n = 10), and used the voxel-based morphometry method to quantify their morphological characteristics. Meanwhile, age- and sex-matched healthy volunteers were included (n = 16). All the participants were neuropsychologically tested to characterize their cognitive function and underwent whole-brain magnetic resonance imaging scanning. Our results showed that the volumes of the bilateral temporal lobes and bilateral frontal gray matter were obviously diminished in the PWMH group. The atrophy volume difference was 4,086 voxels in the left temporal lobe, 4,154 voxels in the right temporal lobe, 1,718 voxels in the left frontal lobe, and 1,141 voxels in the right frontal lobe (P ≤ 0.001). Moreover, the characteristics of the gray matter atrophy associated with the PWMH were more similar to those associated with Alzheimer's disease than SSI, which further revealed the susceptibility for escalation from PWMH to dementia. In conclusion, PWMH patients and SSI patients have different morphological characteristics, which explain the different prognoses of VMCI.

Muscle Health Patterns and Brain MRI Indices: A Cluster Analysis.

The interplay between muscle and brain lacks a holistic approach to assess the combined effect of multiple factors. This study utilizes clustering analysis to identify muscle health patterns and their relationships with various brain magnetic resonance imaging (MRI) indices. Two hundred and seventy-five cognitively intact participants who completed brain MRI from the Health, Aging, and Body Composition Study were enrolled. Muscle health-related markers that showed significant relationship with total gray matter volume entered the cluster analysis. Subsequently, macrostructural and microstructural MRI indices were examined with analysis of variance and multiple linear regression analysis to determine significant associations with muscle health clusters. The muscle health cluster included 6 variables: age, skeletal muscle mass index, gait speed, handgrip strength, change of total body fat, and serum leptin level. Clustering method produced 3 clusters which had characteristics of obese, leptin-resistant, and sarcopenia, respectively. Brain MRI indices that revealed significant associations with the clusters included gray matter volume (GMV) in cerebellum (p < .001), superior frontal gyrus (p = .019), inferior frontal gyrus (p = .003), posterior cingulum (p = .021), vermis (p = .045), and gray matter density (GMD) in gyrus rectus (p < .001) and temporal pole (p < .001). The leptin-resistant group had most degree of reduction in GMV, whereas the sarcopenia group had most degree of reduction in GMD. The leptin-resistant and sarcopenia populations had higher risk of neuroimaging alterations. Clinicians should raise awareness on the brain MRI findings in clinical settings. Because these patients mostly had central nervous system conditions or other critical illnesses, the risk of sarcopenia as a comorbidity will substantially affect the prognosis and medical care.

Right inferior frontal gyrus gray matter density mediates the effect of tolerance of ambiguity on scientific problem finding

Right inferior frontal gyrus gray matter density mediates the effect of tolerance of ambiguity on scientific problem finding

Brain insulin signaling and neurodegeneration: IRS‐1 isolated from neuronal enriched extracellular vesicles associates with frontal lobe gray matter volume in cognitively unimpaired adults

AbstractBackgroundBrain insulin signaling, as measured by insulin signaling proteins in neuronal enriched extracellular vesicles (nEVs), has previously been associated with gray matter (GM) volume in the temporal lobe of nondemented older adults and in multiple brain regions in those with Alzheimer’s clinical syndrome (Walker et al, 2021; Mullins et al, 2017). We sought to extend these findings by performing a voxel‐wise analysis to test the relationship between whole‐brain GM volume and nEV tyrosine phosphorylated IRS‐1 (pY‐IRS‐1) in a cognitively unimpaired sample enriched for AD risk.MethodCognitively‐unimpaired adults (n=47) from the Wisconsin Registry for Alzheimer’s Prevention underwent MRI and blood collection (Table 1). nEVs were isolated from plasma samples by immunoprecipitation targeting neuronal marker L1CAM. pY‐IRS‐1 was measured in nEVs using an electrochemiluminescence assay (Meso Scale Discovery, Rockville, Maryland) (Mustapic et al, 2017). T1‐weighted images were analyzed using the FMRIB Software Library (FSL), where images were first normalized to MNI space and segmented into WM, GM, and CSF using FSL’s FLIRT, FNIRT, and FAST tools and resulting GM maps were smoothed with a Gaussian kernel (sigma = 3.5mm). General linear models and non‐parametric testing (FSL randomise) were used to assess voxelwise associations between nEV pY‐IRS‐1 concentration and GM volume, while controlling for sex and age effects. Significant associations between GM volume and nEV pY‐IRS‐1 were defined as p &lt; 0.01, uncorrected.ResultWe observed lateralized positive associations between nEV pY‐IRS‐1 and GM volume in the right frontal lobe (Figures 1 and 2). After correcting for multiple comparisons, we observed no significant relationships between nEV pY‐IRS‐1 concentration and GM volume.ConclusionPrevious studies indicate that lower nEV pY‐IRS‐1 is associated with lower GM volume in regions such as the temporal and parietal lobes. Here, we determined that lower nEV pIRS‐1 concentrations were associated with lower GM volume laterally in the right frontal lobe of healthy middle‐aged and older adults. Future studies are needed to determine the mechanism by which disrupted insulin signaling in the brain may cause GM loss in these regions.

Longitudinal evolution of neuropathological substrates of Alzheimer’s disease in obese patients

AbstractBackgroundObesity is a metabolic condition with increasing prevalence all over the world. Patients with a body mass index (BMI) higher than 30 are considered obese. Obesity is also a risk factor for chronic morbidities such as type 2 diabetes and may increase the risk of developing Alzheimer's disease (AD). Not much is known about longitudinal changes in Alzheimer’s pathology in these patients. We hypothesised that BMI would predict longitudinal pathological alterations derived from imaging parameters.Method252 participants (n=107 obese non‐diabetic patients with BMI&gt;30) cognitively normal (n=80) and with mild cognitive impairment (n=172) were evaluated from the Alzheimer’s Disease Neuroimaging Initiative (Mean age = 73.6 years, SD = 8.0). All participants had two T1‐weighted MPRAGE MRI scans within two‐years (Mean gap=718 days, SD=107). Regional cortical thickness was measured on T1‐MPRAGE using FreeSurfer v.6.0. Individual gray matter density maps were computed using voxel‐based morphometry (VBM) and regional values were sampled in various cortical regions. Regional cortical thickness and gray matter density are expressed as delta values between baseline and followup (Value followup ‐ Value Baseline). Spearman’s correlation coefficients were calculated to assess the relationship between BMI and imaging biomarkers.ResultIn the whole cohort, we found that BMI is significantly negatively correlated with longitudinal changes in cortical thickness in anterior cingulate (ACC, p=0.0073, r=‐0.17) and posterior cingulate (PCC, p=0.0147, r=‐0.15) cortical thickness. We also found that BMI is significantly negatively correlated with longitudinal changes in frontal (p=0.0184, r=‐0.15), parietal (p=0.0057, r=‐0.18) and temporal (p=0.0141, r=‐0.16) gray matter density. When looking only at MCI participants, we found similar results with even stronger correlations. BMI is significantly negatively correlated with delta anterior cingulate (ACC, p=0.0008, r=‐0.25) and posterior cingulate (PCC, p=0.004, r=‐0.22) cortical thickness.ConclusionIn this cohort of obese and non‐obese participants cognitively normal and with MCI, we found that obesity was associated with a longitudinal 2‐years worsening of macrostructural changes. Higher BMI was associated with a higher reduction of cortical thickness and with a decreased gray matter density in several brain regions.

NIMG-14. RADIOLOGIC ASSESSMENT OF BRAIN METASTASES UNDERGOING LASER INTERSTITIAL THERMAL THERAPY (LITT)

Abstract BACKGROUND Laser Interstitial Thermal Therapy (LITT) is a novel treatment for brain metastases (BMs), and data regarding radiologic changes and long-term efficacy is sparse. This study explored volumetric changes in responding and non-responding BMs and their associations with lesion-specific progression-free survival (PFS-L). METHODS Patients with BMs treated with LITT were retrospectively enrolled. 3D volumes-of-interest of the contrast-enhancing BM tissue (CE) on pre-, post-LITT, and follow-up MRI scans were obtained. BMs were followed until progression or censoring. PFS-L was determined using the modified RANO criteria to assess treatment efficacy on each lesion. RESULTS Thirty-one BMs (from 30 patients) were preliminarily analyzed. 2 BMs had no follow-up scans. Median follow-up for 29 BMs was 248 days (range 28-2200). Median time to response was 430 days (responders n=7/29), median time to progression was 176 days (progressive disease n=7/29). Pre-LITT CE volume was a predictor of PFS-L (p=0.001), with BMs&amp;gt; 2.5 cc being 14 times more likely to undergo progression. Differences in age and primary tumor site did not impact PFS-L, whereas PFS-L tended to be longer in females (p=0.059), and in frontal and deep grey matter BMs (p=0.11). Post-LITT CE volume was higher than pre-LITT (p&amp;lt; 0.0001, median increase 59%), with no significant differences among responders, stable disease, and progressive disease. In each responding BM, the CE volume shrinkage over time was described by an exponential decay (R2 ranging 0.92-1.0 and half-life ranging 16.55-204 days). All responding BMs showed a pooled exponential decay with R2=0.88 and half-life=75.6 days. CONCLUSIONS Our data suggest that smaller BMs may have improved outcomes from LITT treatment. CE volumes may increase in the early post-procedural scans, possibly due to both inflammatory changes and thermal damage. The characterization of the volumetric changes across time for responding lesions may be useful for an early detection of BMs at risk for progression.

NIMG-21. INTERIM ANALYSIS OF A PHASE II STUDY OF MULTIPARAMETRIC MR-GUIDED HIGH-DOSE RESPONSE-ADAPTIVE RADIOTHERAPY WITH CONCURRENT TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA

Abstract BACKGROUND Biologically-informed radiotherapy (RT) targeting an adversely prognostic hypercellular/hyperperfused imaging phenotype in patients with newly diagnosed glioblastoma (GBM) may improve outcomes by identifying emerging regions of treatment resistance associated with survival (OS), and is under investigation in an ongoing Phase II trial (NCT04574856) of individualized, response-adaptive RT. METHODS In this single-arm phase II study, patients with newly diagnosed GBM following resection undergo dose-intensified chemoradiation targeting the residual hypercellular (TVHCV, mean contralateral normal brain+2SD) and hyperperfused tumor volume (TVCBV, contralateral normal frontal grey matter+1SD) identified using high b-value diffusion-weighted and dynamic contrast-enhanced perfusion MRI. The combination of TVHCVCBV (TVHCVCBV) is treated to 50 Gy in 20 fractions (2.5 Gy/fraction), and following mid-RT reassessment, the persistent and developing TVHCVCBV is treated to 30 Gy in 10 fractions (3 Gy/fraction). The primary endpoint is improvement in OS, with planned interim safety analysis. RESULTS Since October 2020, 16 of 30 patients have been enrolled. Median age was 58 years (range, 29-75) and 69% were male. No patient underwent biopsy only, and 50% had gross total resection; 23% had MGMT methylated tumors. Median TVHCV/TVCBV was 6.9 cc (range, 1.9-42.8) pre-RT and 30% (range, 1-72%) was nonenhancing. By mid-RT, TVHCVCBV was reduced to 4.2 cc (range, 0.8-34.3) and 47% (range, 3-74%) was nonenhancing. The TVHCVCBV persisting from pre- to mid-RT was 2.3 cc (range, 0-24.2), with an additional 1.8 cc (range, 0.3-20.6) newly developing outside the initial region. All patients underwent adaptive replanning for boost without interruption. Planned interim analysis determined an acceptable rate of neurologic toxicity and safety to continue enrollment. CONCLUSION Individualized, response adaptive RT using an advanced imaging biomarker to assess emerging and especially non-enhancing regions of treatment resistance in patients with GBM is feasible, with short term safety in an early cohort and longer-term efficacy outcomes anticipated with ongoing accrual.

From Neuroimaging to Computational Modeling of Burnout: The Traditional versus the Fuzzy Approach—A Review

Occupational burnout, manifested by emotional exhaustion, lack of a sense of personal achievement, and depersonalization, is not a new phenomenon, but thusfar, there is no clear definition or diagnostic guidelines. The aim of this article wasto summarize all empirical studies to date that have used medical neuroimaging techniques to provide evidence or links regarding changes in brain function in occupational burnout syndrome from a neuroscientific perspective, and then use these to propose a fuzzy-based computational model of burnout.A comprehensive literature search was conducted in two major databases (PubMed and Medline Complete). The search period was 2006–2021, and searches were limited to the English language. Each article was carefully reviewed and appropriately selected on the basis of raw data, validity of methods used, clarity of results, and scales for measuring burnout. The results showed that the brain structures of patients with job burnout that are associated with emotion, motivation, and empathy weresignificantly different from healthy controls. These altered brain regions included the thalamus, hippocampus, amygdala, caudate, striatum, dorso-lateral prefrontal cortex, anterior cingulate cortex, posterior cingulate cortex, anterior insula, inferior frontal cingulate cortex, middle frontal cingulate cortex, temporoparietal junction, and grey matter. Deepening our understanding of how these brain structures are related to burnout will pave the way for better approaches fordiagnosis and intervention. As an alternative to the neuroimaging approach, the paper presents a late proposal of the PLUS (personal living usual satisfaction) parameter. It is based on a fuzzy model, wherein the data source is psychological factors—the same or similar to the neuroimaging approach. As the novel approach to searching for neural burnout mechanisms, we have shown that computational models, including those based on fuzzy logic and artificial neural networks, can play an important role in inferring and predicting burnout. Effective computational models of burnout are possible but need further development to ensure accuracy across different populations. There is also a need to identify mechanisms and clinical indicators of chronic fatigue syndrome, stress, burnout, and natural cognitive changes associated with, for example, ageing, in order to introduce more effective differential diagnosis and screening.

Executive Dysfunction, Social Cognition Impairment, and Gray Matter Pathology in Myotonic Dystrophy Type 2: A Pilot Study.

In contrast to myotonic dystrophy type 1, the cognitive and radiologic profile of myotonic dystrophy type 2 (DM2) is relatively poorly characterized. To conduct a pilot study to systematically evaluate cognitive and radiologic features in a cohort of Greek individuals with DM2. Eleven genetically confirmed individuals with DM2 and 26 age- and education-matched healthy controls were administered the Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis Screen (ECAS) to screen for impairment in multiple cognitive domains. MRI data were evaluated by morphometric analyses to identify disease-specific gray and white matter alterations. The following statistical thresholds were used for cognitive comparisons: PFDR < 0.05 and Bayes factor (BF 10 ) >10. The DM2 group exhibited cognitive impairment (ECAS Total score; PFDR = 0.001; BF 10 = 108.887), which was dominated by executive impairment ( PFDR = 0.003; BF 10 = 25.330). A trend toward verbal fluency impairment was also identified. No significant impairments in memory, language, or visuospatial function were captured. The analysis of subscores revealed severe impairments in social cognition and alternation. Voxel-based morphometry identified widespread frontal, occipital, and subcortical gray matter atrophy, including the left superior medial frontal gyrus, right medial orbitofrontal gyrus, right operculum, right precuneus, bilateral fusiform gyri, and bilateral thalami. DM2 may be associated with multifocal cortical and thalamic atrophy, which is likely to underpin the range of cognitive manifestations mostly characterized by executive impairment and specifically by impaired social cognition.

Interhemispheric asymmetry of the brain in patients with type 1 diabetes mellitus and cognitive impairment.

With an ageing of population and a splurging epidemic of diabetes mellitus (DM), the prevalence of complications associated with pathology of the central nervous system are expected to increase, which in the future may have serious consequences for public health. It is known that one of the main manifestations of brain damage in type 1 diabetes is cognitive impairment, which is possibly associated with the peculiarities of vascularization and interhemispheric asymmetry, which requires in-depth analysis using modern neuroimaging methods. The aim of the study is to assess the symmetry of structural, metabolic and neurovascularization changes in the brain in patients with type 1 diabetes and cognitive impairment. The study included 120 patients with type 1 diabetes aged 18 to 45 years suffering from cognitive impairment, and 30 people without cognitive decline and the control group (n=30) healthy people without diabetes. Neuropsychological testing included the Montreal Cognitive Dysfunction Assessment Scale (MoCA test). For neuroimaging methods, standard magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), contrast and non-contrast-enhanced perfusion were used. Statistical processing was carried out using the SPSS Statistic 2020 software. In patients with type 1 diabetes with cognitive impairment, as manifested by impaired memory and/or attention, perfusion imaging revealed the presence of brain asymmetry zones. Standard MRI allowed to demonstrate changes in the white, gray matter and hippocampus in the right hemisphere. The results obtained were refined taking into account the topical localization, so during the perfusion study, regions with asymmetric blood flow were identified - namely, the white matter of the frontal lobe and the gray matter in the occipital lobe. Spectroscopy of the brain revealed that it was in these areas of the brain that the most significant metabolic disorders were noted – in the form of significantly altered ratio of N-acetylaspartate (NAA)/choline (Cho) on the left, along with the asymmetry in phosphocreatine level (Cr 2) on the right. In conclusion, early preclinical predictive diagnostics with the use of modern neuroimaging methods allows for timely detection of impaired vascularization and brain metabolism in this group of patients, However, decreased perfusion in the region within the region of frontal lobe white matter and temporal lobe grey matter, and hippocampal cell metabolism by spectra should be highlighted among the parameters Cr right and NAA/Cho left.

PRE- AND POST- SHUNT CEREBRAL PERFUSION MEASURED BY DYNAMIC SUSCEPTIBILITY CONTRAST MRI IN PATIENTS WITH NORMAL PRESSURE HYDROCEPHALUS.

Background: NPH-related dementia is the only surgically manageable dementia. Response to ventricular shunting in NPH is variable. This study aims to establish a possible correlation between the changes in cerebral perfusion with clinical response to shunting. The study group consisted of Methods: 20 patients with NPH diagnoses who underwent ventricular shunting. Pre- and 3-month post- shunt DSC-MRI was done to assess the change in relative cerebral blood ow (rCBF). Mean ± SD values of rCBF in frontal grey matter, frontal periven Results: tricular white matter, parietal periventricular white matter and hippocampus were 0.91 ± 0.11, 0.61 ± 0.09, 0.47 ± 0.11 and 0.93 ± 0.06 before shunt surgery and 0.98 ± 0.06, 0.70 ± 0.07, 0.54 ± 0.07 and 0.98 ± 0.06 after shunt surgery in NPH patients who responded to shunt surgery; and 0.78 ± 0.17, 0.37 ± 0.14, 0.41 ± 0.11 and 0.89 ± 0.10 before shunt surgery and 0.79 ± 0.14, 0.37 ± 0.19, 0.38 ± 0.09 and 0.84 ± 0.07 after shunt surgery in NPH patients who did not respond to shunt surgery. Therefore, regional rCBF in these regions increased in responders after shunt surgery, with a signicant statistical difference (p-value &lt; 0.05) while no signicant change was seen in shunt non-responders (p-value &gt; 0.05). There is a correlation between a si Conclusion: gnicant increase in regional rCBF and clinical improvement after shunt surgery.

Ongoing oxidative stress in individuals with post-acute sequelae of COVID-19.

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection is associated with lower plasma glutathione (GSH) levels due to oxidative stress. However, plasma levels may not reflect brain GSH levels. Individuals with post-acute sequelae of COVID-19 (PASC) have a higher prevalence of cognitive fatigue, which might be related to altered brain γ-aminobutyric-acid (GABA) levels. Hence, our study aims to measure the brain GSH and GABA levels in PASC. 29 PASC participants and 24 uninfected controls were recruited for this study. Each was evaluated with detailed neuropsychiatric assessments and an edited proton MRS (Hadamard Encoding and Reconstruction of Mega-Edited Spectroscopy, HERMES) method to measure GABA and GSH concentrations in predominantly grey matter (GM) and predominantly white matter (WM) brain frontal voxels. PASC participants were 219 ± 137 days since their COVID-19 diagnosis. Nine individuals with PASC were hospitalized. Compared to controls, individuals with PASC had similar levels of GABA in both brain regions, but lower GSH and greater age-related GSH decline in the frontal GM region. The lower-than-normal frontal GM GSH level in participants with PASC suggest that they have ongoing oxidative stress in the brain, and that older individuals may be even more vulnerable to oxidative stress.

Correlations between sleep disturbance and brain structures associated with neurodegeneration in the National Alzheimer's Coordinating Center Uniform Data Set

This study aimed to 1) determine the association between sleep disturbance and brain structure volumes, 2) the moderation effect of apolipoprotein ε4 genotype on sleep disturbance and brain structures, and 3) the moderation effect of sleep disturbance on cognitive status and regional brain volumes.Using the National Alzheimer’s Coordinating Center Uniform Data Set (n = 1,533), multiple linear regressions were used to evaluate the association between sleep disturbance and brain volumes. Sleep disturbance was measured using one question from the NPI-Q.After controlling for intracranial volume, age, sex, years of education, race, ethnicity, and applying the FDR correction, total cerebrospinal fluid volume, left lateral ventricle volume, total lateral ventricle volume, and total third ventricle volume demonstrated significantly higher means for those with sleep disturbance. Total brain volume, total white and gray matter volume, total cerebrum brain volume (including gray but not white matter), left hippocampus volume, total hippocampal volume, the left, right, and total frontal lobe cortical gray matter volume, and the left, right, and total temporal lobe cortical gray matter volume demonstrated significantly lower mean volumes for those with sleep disturbance. Sleep disturbance moderated the association between cognitive status and lateral ventricular volumes. These findings suggest that disrupted sleep is associated with atrophy across multiple brain regions and ventricular hydrocephalus ex vacuo.

NEIM-08 A PHASE II STUDY OF MULTIPARAMETRIC MR-GUIDED HIGH DOSE ADAPTIVE RADIOTHERAPY WITH CONCURRENT TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA

BACKGROUNDBiologically-informed radiotherapy (RT) targeting an adversely prognostic hypercellular/hyperperfused imaging phenotype in patients with newly diagnosed glioblastoma (GBM) may improve outcomes by identifying emerging regions of treatment resistance associated with survival (OS), and is under investigation as a target for individualized, adaptive RT in an ongoing Phase II trial (NCT04574856). METHODSIn this single-arm study, patients with newly diagnosed GBM following resection undergo dose-intensified chemoRT targeting the residual hypercellular (TVHCV, mean contralateral normal brain+2SD) and hyperperfused tumor volume (TVCBV, contralateral normal frontal grey matter+1SD) identified using high b-value diffusion-weighted and dynamic contrast-enhanced perfusion MRI. TVHCV/TVCBV is treated to 50 Gy in 20 fractions (2.5 Gy/fraction), and following mid-RT reassessment, the persistent and developing TVHCV/TVCBV is treated to 30 Gy in 10 fractions (3 Gy/fraction). The primary endpoint is improvement in OS, with planned interim safety analysis. RESULTSSince October 2020, 16 of 30 patients have been enrolled. Median age was 58 years (range, 29-75) and 69% were male. No patient underwent biopsy, and 50% had gross total resection; 23% had MGMT methylated tumors, and all except 2 were IDHwt. Median TVHCV/TVCBV was 6.9 cc (range, 1.9-42.8) pre-RT and 30% (range, 1-72%) was nonenhancing. By mid-RT, TVHCV/TVCBV was reduced to 4.2 cc (range, 0.8-34.3) and 47% (range, 3-74%) was nonenhancing. The TVHCV/TVCBV persisting from pre- to mid-RT was 2.3 cc (range, 0-24.2), with an additional 1.8 cc (range, 0.3-20.6) newly developing outside of the initial region. All patients underwent adaptive replanning for boost without interruption. Planned interim analysis determined an acceptable rate of neurologic toxicity and safety to continue enrollment. CONCLUSIONIndividualized, adaptive radiotherapy using an advanced imaging biomarker to assess emerging and especially non-enhancing regions of treatment resistance in patients with GBM is feasible, with short term safety in an early cohort and longer-term efficacy outcomes anticipated with ongoing accrual.

Frontal grey matter microstructure is associated with sleep slow waves characteristics in late midlife.

The ability to generate slow waves (SW) during non-rapid eye movement (NREM) sleep decreases as early as the 5th decade of life, predominantly over frontal regions. This decrease may concern prominently SW characterized by a fast switch from hyperpolarized to depolarized, or down-to-up, state. Yet, the relationship between these fast and slow switcher SW and cerebral microstructure in ageing is not established. We recorded habitual sleep under EEG in 99 healthy late midlife individuals (mean age = 59.3 ± 5.3 years; 68 women) and extracted SW parameters (density, amplitude, frequency) for all SW as well as according to their switcher type (slow vs. fast). We further used neurite orientation dispersion and density imaging (NODDI) to assess microstructural integrity over a frontal grey matter region of interest (ROI). In statistical models adjusted for age, sex, and sleep duration, we found that a lower SW density, particularly for fast switcher SW, was associated with a reduced orientation dispersion of neurites in the frontal ROI (p = 0.018, R2β* = 0.06). In addition, overall SW frequency was positively associated with neurite density (p = 0.03, R2β* = 0.05). By contrast, we found no significant relationships between SW amplitude and NODDI metrics. Our findings suggest that the complexity of neurite organization contributes specifically to the rate of fast switcher SW occurrence in healthy middle-aged individuals, corroborating slow and fast switcher SW as distinct types of SW. They further suggest that the density of frontal neurites plays a key role for neural synchronization during sleep. EudraCT 2016-001436-35.

Pattern of Altered Magnetization Transfer Rate in Alzheimer's Disease.

Biomarkers for Alzheimer's disease (AD) are crucial for early diagnosis and treatment monitoring once disease modifying therapies become available. This study aims to quantify the forward magnetization transfer rate (kfor) map from brain tissue water to macromolecular protons and use it to identify the brain regions with abnormal kfor in AD and AD progression. From the Cardiovascular Health Study (CHS) cognition study, magnetization transfer imaging (MTI) was acquired at baseline from 63 participants, including 20 normal controls (NC), 18 with mild cognitive impairment (MCI), and 25 AD subjects. Of those, 53 participants completed a follow-up MRI scan and were divided into four groups: 15 stable NC, 12 NC-to-MCI, 12 stable MCI, and 14 MCI/AD-to-AD subjects. kfor maps were compared across NC, MCI, and AD groups at baseline for the cross-sectional study and across four longitudinal groups for the longitudinal study. We found a lower kfor in the frontal gray matter (GM), parietal GM, frontal corona radiata (CR) white matter (WM) tracts, frontal and parietal superior longitudinal fasciculus (SLF) WM tracts in AD relative to both NC and MCI. Further, we observed progressive decreases of kfor in the frontal GM, parietal GM, frontal and parietal CR WM tracts, and parietal SLF WM tracts in stable MCI. In the parietal GM, parietal CR WM tracts, and parietal SLF WM tracts, we found trend differences between MCI/AD-to-AD and stable NC. Forward magnetization transfer rate is a promising biomarker for AD diagnosis and progression.