Cerebrospinal Fluid Volume Research Articles

Analysis of blood and cerebrospinal fluid flows in preclinical AD. Preliminary results from ALFA+ cohort

AbstractBackgroundIntracranial cerebrospinal fluid (CSF) motion is driven by the wave pressure associated with arterial blood flow into the skull (Figure 1). Since one of the roles of CSF is the clearance of neural waste, it was investigated the relationship between blood and CSF flow parameters (as measured by magnetic resonance imaging [MRI]) and CSF Ab42/40 and ptau‐181 levels in the preclinical stages of Alzheimer’s disease (AD).MethodThree hundred sixty‐five subjects from the ALFA+ cohort underwent two MRI phase‐encoded velocity sequences (30 frames per cardiac cycle) to measure (1) blood flow in carotids below carotid bifurcation and (2) CSF flow through foramen magnum. The scanner’s Q‐flow tool was used to quantify stroke volume (volume per cardiac cycle), percent of vessel’s area increase and flow velocity increase, as a proxy for vessel elasticity and flow pulsatility, respectively. Associations between flow parameters and age, CSF Ab42/40 and ptau‐181 concentrations were sought, correcting for sex, age and time between lumbar puncture and MRI (P<0.05).ResultOne hundred thirty‐two subjects were excluded because the scanning session was not completed, showed missing or outlier values or did not pass quality control (artifacts or unbalanced outwards‐inwards CSF flow measures), resulting in a final sample size of 233 participants (mean age [SD]: 60.8±4.5 years; male: n = 73 [31.3%]). Figure 2 shows the plots with the most significant relationships between flow parameters, CSF biomarkers, CSF volume and age. It was observed that a higher stroke volume in CSF flow was associated with lower Ab42/40 and higher ptau‐181 concentrations in CSF.ConclusionThese results indicate that, despite the role of CSF in waste clearance, the accumulation of amyloid and tau in the brain might be neither caused nor enhanced by a global deficit in CSF circulation. We hypothesize that a higher volume of CSF associated with age and high ptau‐181 levels and/or the loss of parenchyma elasticity might reduce the global intracranial compressibility, resulting in an enhanced response to pressure increase due to blood flow into the skull, which could explain the observed increase in CSF flow associated with the early stages of AD.

Hippocampal subfield volume in relation to cerebrospinal fluid Amyloidβ1‐42 in early Alzheimer’s disease: A 7T MRI study

AbstractBackground7T MRI can provide high contrast and spatial resolution images for studying the volume of hippocampal subfields which can be used in conjunction with Amyloidβ1‐42 and tau measures in the cerebrospinal fluid (CSF) to provide a non‐invasive alternative marker for Alzheimer’s disease (AD).Method41 participants (20 AD and 21 healthy age‐ and gender‐matched controls) were recruited [aged 40 ‐ 76 years; 64% female). The protocol for the analysis of the CSF for the Amyloidβ1‐42 (reference range: 627‐1322 pg/ml), total tau (reference range: 146‐595 pg/ml), Thr181‐phosphorylated tau (reference range <68 pg/ml) have been previously published (Hosseini et al, 2022) and the measures were used for the ATN classification of Alzheimer’s disease. Imaging was carried out on a Philips Achieva 7T scanner using a Nova Medical (Wilmington MA, USA) single‐channel transmit, 32‐channel receive (1Tx32Rx) head coil. Images acquired are PSIR (TE/TR = 3.1/6.9ms; FA = 6o, isotropic 0.55 mm resolution) and T2‐weighted FSE (TE/TR = 119/59001ms, FA = 90o, 0.38×0.39×1.50 mm3 resolution).ResultFig 1 show the T2‐weighted image and the segmentation of the hippocampus obtained using ASHS (Yushkevich et al., 2015b)There was a significant decrease in the volume of each hippocampal subfield (Fig2) in AD patients compared to controls. The change in volume was not significant for the whole brain showing that the hippocampal volume loss was not simply part of general brain atrophy.There was an approximately linear relationship between the CSF Amyloidβ1‐42 and volume of the hippocampus for the AD participants (Fig 3). A positive linear relationship was observed in all the subfields of the hippocampus but a statistically significant relation was only achieved in the Entorhinal Cortex (ERC) [p<0.022, r = 0.508].The ERC is known to represent perception of time, memory and navigation (Tsao et al., 2018)(Du et al., 2001), and AD pathology may start from the ERC before migrating along the hippocampus (Braak & Braak, 1997). Further, the ERC volume loss on 1.5 T MRI has been reported greater in AD as compared with Mild Cognitive Impairment(Du et al., 2001).ConclusionThe association of the volume of ERC and CSF Amyloidβ1‐42 suggests the potential for using 7T MRI as a biomarker for an early identification of AD.

Association of ambient air pollution with cognitive functioning and structural brain damage: The Maastricht Study

AbstractBackgroundDementia prevention poses one of the biggest challenges to our ageing society (1,2). Next to individual modifiable risk factors, shared environmental risk factors have been linked to dementia risk. Exposure to air pollution has been identified as a new candidate risk factor which on a population level carries more risk than well‐established risk factors such as hypertension and type‐2 diabetes (1). This study aimed to investigate the association between exposure to air pollutants with cognitive functioning and markers of structural brain damage next to and above individual risk factors.MethodCross‐sectional data from the population‐based cohort (N = 4,154; mean age 59.27±8.54 years, 50.12% women) of The Maastricht Study (3) was used and matched to address‐based data from the Geoscience andHealth Cohort Consortium of average exposure to particulate matter (<2.5mg and <10mg), NO2 and soot over the years 2013‐2018. Cognitive functioning was assessed through a neuropsychological test battery. Standardized volumes of grey matter, white matter, cerebrospinal fluid, and presence of cerebral small vessel disease were derived from 3‐Tesla MRI. Individual risk factors were added as one covariate, using the validated Lifestyle for Brain Health score (4). Binary logistic and multiple linear regression analyses tested the associations between air pollutants and the outcome measures. Likelihood‐ratio tests were performed to compare the extensive models.ResultWe found a curvilinear association relating particulate matter exposure in the mid to higher range to lower grey matter and higher cerebrospinal fluid volume, independent of age, sex, education, and LIBRA score. There was no association between air pollutant exposure and cognitive functioning or markers of cerebral small vessel disease.ConclusionIn this population‐based cohort, average to high exposure to particulate matter was related to an increase in markers of brain atrophy, showing important implications for environmental and public health policymaking.

The associations of socioeconomic status with structural brain damage and connectivity and cognition: The Maastricht Study

AbstractBackgroundSocioeconomic inequalities in the risk for cognitive impairment have been reported, which might partly act through structural brain damage or differential numbers of brain connections (structural connectivity). This study investigated the extent to which the association of early‐life socioeconomic status (SES) with later‐life cognitive performance is mediated by later‐life SES, and whether the association of SES with later‐life cognitive performance can be explained by structural brain damage and connectivity.MethodWe used cross‐sectional data from the population‐based Maastricht study (n = 4,839; mean age 59.2±8.7 years, 49.8% women). Early‐life SES was assessed retrospectively by self‐reported poverty and parental education. Later‐life SES included education, occupation, and household income. Participants underwent cognitive testing and 3 T magnetic resonance imaging to measure volumes of white matter hyperintensities, gray matter, white matter, cerebrospinal fluid, and structural connectivity. Multiple linear regression analyses tested the associations between SES, brain markers and cognition. Analyses were adjusted for age, sex, and type 2 diabetes (because of oversampling). Structural equation modeling tested mediation.ResultHigher SES was associated with higher grey matter volume, lower white matter volume, and higher structural connectivity. Structural brain damage and lower structural connectivity were associated with lower overall cognitive performance. Both higher early‐life and later‐life SES were associated with overall higher cognitive performance (B [95% CI] medium versus low early‐life SES = 0.17[0.12;0.23]; B high versus low early‐life SES = 0.26[0.20;0.32]; B medium versus low later‐life SES = 0.46[0.41;0.52]; B high versus low later‐life SES = 0.72[0.67;0.78]). The association of early‐life SES with later‐life cognitive performance was partly mediated by later‐life SES (73.8%). The extent to which the association of SES with cognitive performance could be explained by structural brain damage or connectivity was marginal (up to 5.9%).ConclusionThough there was an association between early‐life SES and later‐life cognitive performance independent of later‐life SES, a large part of this association could be explained by later‐life SES. Structural brain damage and connectivity marginally explained socioeconomic inequalities in cognitive performance. More research is needed to investigate alternative pathways that explain associations of life‐course SES with later‐life cognition.

Mediterranean diet protects against neuroinflammation and degeneration in female nonhuman primates

AbstractBackgroundMediterranean diets may reduce Alzheimer’s disease (AD) risk and preserve cognitive function relative to Western diets in part by protecting against neuroinflammation. In middle‐aged humans that subsequently develop AD, increased cortical thickness precedes atrophy. It is hypothesized that the initial increase in brain volumes may be due to early neuroinflammation that precedes neurodegeneration (Pegueroles et al. Alzheimers Dement 2017). Long term impacts of diet patterns on health are difficult to quantify in human beings. Thus, we addressed this hypothesis in cynomolgus macaques (Macaca fascicularis), a nonhuman primate that undergoes age‐related changes in brain structure and function, and responds to Western diets, like humans.Method38 middle‐aged (mean = 12 years of age) female macaques were fed a Western or Mediterranean diet for 2.5 years in a randomized nonhuman primate trial. Changes from baseline in volumes of total brain, gray, cortical gray, and white matter, cerebrospinal fluid and (CSF), were determined by structural MRI. We also generated thickness‐based AD temporoparietal meta‐ROIs based on the AD clinical literature as previously described (Frye et al., 2021 Alzheimers Dement. 2021;17:733). Transcriptional profiles in the temporal cortex were determined at the end of the study by RNAseq.ResultWestern diet led to increases in temporoparietal cortical thicknesses, total brain and gray matter volumes, and diminished cerebrospinal fluid and white matter volumes. Diet significantly altered expression of seven genes (FDR<0.05). The Mediterranean group had lower expression of CDK14, a proinflammatory regulator, and higher expression of BTN2A1, KATNB1, LFNG, MRC2, SLCA32, and TMEM268, many of which have anti‐inflammatory associations. Several differentially expressed genes were correlated with AD‐relevant brain volumes. CDK14 was positively correlated with total brain, total gray, and cortical gray matter volumes and temporoparietal cortical thickness (Figure, Mediterranean = yellow), and negatively correlated with total white matter and CSF volumes. LFNG, MRC2, and SLCA32 were negatively correlated with total brain, total gray, and cortical gray matter volume, as well as temporoparietal cortical thickness, and positively correlated with CSF volume (all p’s<0.05).ConclusionThese results suggest that the Mediterranean diet protects against, whereas the Western diet promotes, AD‐relevant neuroinflammation associated with early increases in gray matter volumes.

Changes in Brain Glutathione in patients with mild vascular cognitive impairment

AbstractBackgroundOxidative stress (OS) has been implicated in age‐related neurodegeneration and may be important in prodromal states such as mild vascular cognitive impairment (mVCI). Higher peripheral OS is reported in mVCI patients; however, the role of central antioxidant defenses in mVCI is unclear. Glutathione (GSH) is a major brain antioxidant, and so brain GSH in possible mVCI vs. controls was assessed.MethodPossible mVCI patients (1 standard deviation (SD) below population norms in verbal memory, executive function (EF), processing speed, or working memory, age 55‐85, and currently enrolled in a cardiac rehabilitation program due to having 2 or more vascular risk factors or previous vascular event) and cognitively‐normal (CN) controls are recruited from a 6‐month exercise rehabilitation program. All participants received 1H magnetic resonance spectroscopy (MEscher–GArwood Point Resolved Spectroscopy) to quantify brain GSH at baseline in the anterior cingulate (AC) and occipital region (OC). Spectroscopic analysis was completed using the Gannet toolkit (vers. 3.1) in Matlab (vers. 2020b), a cut‐off of 20% was used to reject spectra of poor quality.ResultIn 30 participants (mVCI n = 16, CN n = 14), anterior cingulate (AC) GSH (I.U. ± SD) was higher in mVCI (1.86 ± 0.45) compared to CN (1.63 ± 0.50) (F(1,18.8) = 4.6, P = 0.04), this difference became trending after correcting for cerebrospinal fluid volume ((F(1,18.2) = 3.9, P = 0.06). No difference was detected for OC‐GSH before or after correcting for cerebrospinal fluid volume. Higher AC‐GSH was correlated with lower Montreal Cognitive Assessment score (rho (26) = ‐0.42, p = 0.02).ConclusionPreliminary data suggest an upregulation in anterior cingulate glutathione in mVCI, which might reflect a compensatory increase in antioxidants as a response to increase peripheral oxidative stress previously reported in these patients. Recruitment is ongoing and additional participants are needed to reinforce findings.

Brain glutathione may be associated with white matter hyperintensities in patients with cardiovascular disease

AbstractBackgroundWhite matter hyperintensity (WMH) is a marker of age‐related cerebrovascular damage and is correlated with cognitive impairment; ischemia and inflammatory mechanisms have been proposed to be involved in its pathogenesis. These processes are associated with oxidative stress (OS), which may impair cellular function and affect antioxidant balance; however, the role of central antioxidant responses is still unclear.MethodPatients (age 55‐85) with ≥2 vascular risk factors or a previous vascular event were assessed at baseline for an exercise rehabilitation program. All participants completed the Montreal Cognitive Assessment (MoCA). Baseline WHM severity was determined using the standardized Canadian Dementia Imaging Protocol and semiautomatic protocols. Brain glutathione (GSH) at baseline was obtained in the anterior cingulate (AC) and occipital region (OC) using 1H magnetic resonance spectroscopy (MEscher–GArwood Point Resolved Spectroscopy). Spectroscopic analysis was completed using the Gannet toolkit (vers. 3.1) in Matlab (vers. 2020b).ResultOf 30 participants (mean age: 66.2 ± 7.42 SD; 80% male) currently enrolled, brain volumetric measurements were completed for 25 participants. Lower MoCA score was associated with greater total WMH volume, controlling for age (b[SE] = ‐0.017 [0.005], t(22) = ‐3.24, p = 0.004); this relationship remained significant when controlling for years of education separately (b[SE] = ‐0.016 [0.006], t(22) = ‐2.86, p = 0.01). Correcting for cerebrospinal fluid volume, lower AC‐GSH level was associated with higher deep WMH volume in the medial middle frontal (MMF) region of interest (b[SE] = ‐0.056 [0.023], t(23) = ‐2.38, p = 0.026), but not with MMF paraventricular WMH volume. After controlling for age, the model was no longer significant (F (2, 22) = 2.87, p = 0.078). No significant associations were found between OC‐GSH and occipital lobe WMH.ConclusionAs expected, total white matter hyperintensity volume was associated with poorer global cognition. In the medial middle frontal (MMF) region of interest, higher deep WMH was associated with lower GSH levels, suggesting altered brain antioxidant levels may be associated with the presence or formation of WMH. Recruitment is ongoing, and additional participants are needed to reinforce findings and to control for confounders in the analysis.

A Systematic Characterization of Structural Brain Changes in Epilepsy Using Magnetic Resonance Imaging

Grey matter and white matter changes in epilepsy detected by Voxel-based morphometry (VBM) and Tensor-based morphometry (TBM) show notable similarities and differences to date. Therefore, a direct comparison of results using VBM and TBM is necessary to understand how different methods are sensitive in detecting structural brain changes in epilepsy. 45 patients with epilepsy (27.62 ±12.8 years old) and 46 healthy controls (34.25 ±16.0 years old) were scanned using a 3 Tesla MRI scanner. T1 weighted brain images were acquired, pre-processed, and further analyzed using Computational Anatomy Toolbox (CAT12). For VBM, voxel-wise grey matter volumes, white matter volumes and cerebrospinal fluid volumes were computed and smoothed (Full width at half maximum, FWHM= 8 mm) for each participant. For TBM, voxel-wise Jacobian determinant images were obtained and smoothed (FWHM= 8 mm). The group differences between patients and healthy controls were obtained using two-sample T-tests. Conjunction analyses were performed to explore the sensitivity of different methods in detecting grey matter and white matter. Our results showed that although both methods detected widespread structural changes, there are similarities and differences in grey matter and white matter findings detected by different methods. Only 35.07 % of grey matter (cerebellum, right temporal gyrus, left cuneus and left superior frontal) were commonly detected by VBM and TBM while only 26.08 % of white matter (anterior lobe of cerebellum, left occipital, frontal, and right temporal regions) were commonly detected by VBM and TBM. Therefore, we conclude that VBM and TBM are differently sensitive in detecting structural brain changes in epilepsy.

Recurrent reflex syncope in idiopathic intracranial hypertension patient resolved after lumbar puncture: pathogenetic implications

BackgroundIdiopathic intracranial hypertension is a disease characterized by increased intracranial cerebrospinal fluid volume and pressure without evidence of other intracranial pathology. Dural sinuses are rigid structures representing a privileged low-pressure intracranial compartment. Rigidity of dural sinus ensures that the large physiologic fluctuations of cerebrospinal fluid pressure associated with postural changes or to Valsalva effect cannot be transmitted to the sinus. An abnormal dural sinus collapsibility, especially when associated with various anatomical sinus narrowing, has been proposed as a key factor in the pathogenesis of idiopathic intracranial hypertension. This pathogenetic model is based on an excessive collapsibility of the dural sinuses that leads to the triggering of a self-limiting venous collapse positive feedback-loop between the cerebrospinal fluid pressure, that compresses the sinus, and the increased dural sinus pressure upstream, that reduces the cerebrospinal fluid reabsorption rate, increasing cerebrospinal fluid volume and pressure at the expense of intracranial compliance and promoting further sinus compression. Intracranial compliance is the ability of the craniospinal space to accept small volumetric increases of one of its compartments without appreciable intracranial pressure rise. In idiopathic intracranial hypertension, a condition associated with a reduced rate of CSF reabsorption leading to its volumetric expansion, a pathologically reduced IC precedes and accompanies the rise of ICP. Syncope is defined as a transient loss of consciousness due to a transient cerebral hypoperfusion characterized by rapid onset, short duration, and spontaneous complete recovery. A transient global cerebral hypoperfusion represents the final mechanism of syncope determined by cardiac output and/or total peripheral resistance decrease. There are many causes determining low cardiac output including reflex bradycardia, arrhythmias, cardiac structural disease, inadequate venous return, and chronotropic and inotropic incompetence. Typically, syncopal transient loss of consciousness is mainly referred to an extracranial mechanism triggering a decrease in cardiac output and/or total peripheral resistance. Conversely, the association of syncope with a deranged control of intracranial compliance related to cerebral venous outflow disorders has been only anecdotally reported.Case PresentationWe report on a 57-year-old woman with daily recurrent orthostatic hypotension syncope and idiopathic intracranial hypertension-related headaches, which resolved after lumbar puncture with cerebrospinal fluid subtraction.ConclusionsA novel mechanism underlying the triggering of orthostatic syncope in the presence of intracranial hypertension-dependent reduced intracranial compliance is discussed.

Brain Volume in Fetal Alcohol Spectrum Disorders Over a 20-Year Span

Anomalous brain development and mental health problems are prevalent in fetal alcohol spectrum disorders (FASD), but there is a paucity of longitudinal brain imaging research into adulthood. This study presents long-term follow-up of brain volumetrics in a cohort of participants with FASD. To test whether brain tissue declines faster with aging in individuals with FASD compared with control participants. This cohort study used magnetic resonance imaging (MRI) data collected from individuals with FASD and control individuals (age 13-37 years at first magnetic resonance imaging [MRI1] acquired 1997-2000) compared with data collected 20 years later (MRI2; 2018-2021). Participants were recruited for MRI1 through the University of Washington Fetal Alcohol Syndrome (FAS) Follow-Up Study. For MRI2, former participants were recruited by the University of Washington Fetal Alcohol and Drug Unit. Data were analyzed from October 2022 to August 2023. Intracranial volume (ICV) and regional cortical and cerebellar gray matter, white matter, and cerebrospinal fluid volumes were quantified automatically and analyzed, with group and sex as between-participant factors and age as a within-participant variable. Of 174 individuals with MRI1 data, 48 refused participation, 36 were unavailable, and 24 could not be located. The remaining 66 individuals (37.9%) were rescanned for MRI2, including 26 controls, 18 individuals with nondysmorphic heavily exposed fetal alcohol effects (FAE; diagnosed prior to MRI1), and 22 individuals with FAS. Mean (SD) age was 22.9 (5.6) years at MRI1 and 44.7 (6.5) years at MRI2, and 35 participants (53%) were male. The FAE and FAS groups exhibited enduring stepped volume deficits at MRI1 and MRI2; volumes among control participants were greater than among participants with FAE, which were greater than volumes among participants with FAS (eg, mean [SD] ICV: control, 1462.3 [119.3] cc at MRI1 and 1465.4 [129.4] cc at MRI2; FAE, 1375.6 [134.1] cc at MRI1 and 1371.7 [120.3] cc at MRI2; FAS, 1297.3 [163.0] cc at MRI1 and 1292.7 [172.1] cc at MRI2), without diagnosis-by-age interactions. Despite these persistent volume deficits, the FAE participants and FAS participants showed patterns of neurodevelopment within reference ranges: increase in white matter and decrease in gray matter of the cortex and decrease in white matter and increase in gray matter of the cerebellum. The findings of this cohort study support a nonaccelerating enduring, brain structural dysmorphic spectrum following prenatal alcohol exposure and a diagnostic distinction based on the degree of dysmorphia. FASD was not a progressive brain structural disorder by middle age, but whether accelerated decline occurs in later years remains to be determined.

Total-Body Irradiation Alters White Matter Volume and Microstructural Integrity in Rhesus Macaques

Long-term survivors of brain irradiation can suffer from irreversible injury and cognitive impairment. T1-weighted and diffusion tensor magnetic resonance imaging are used to evaluate brain volumes and white matter (WM) microstructure in neurodevelopmental and neurodegenerative conditions. The goal of this study was to evaluate the long-term effects of single-dose total-body irradiation (TBI) or TBI with 5% partial-body sparing on brain volumetrics and WM integrity in macaques. We utilized MRI scans from a cohort of male rhesus macaques (age range: 3.6-22.8 years), to compare global and regional brain volumes and WM diffusion in survivors of TBI (T1w: n=137, DTI: n=121, dose range: 3.5-10 Gy) against unirradiated controls (T1w: n=48, DTI: n=38). In all ROIs, radiation affected the age-related changes in fractional anisotropy (FA); in general, FA increased across age in both groups, but to a lesser extent in the irradiated group (interaction p-values <0.01). Depending on the ROI, mean diffusivity (MD) decreased or remained the same across age in unirradiated animals, while it increased or did not change in irradiated animals. The increases in MD were driven by changes in radial diffusivity (RD) which followed similar trends across age. Axial diffusivity (AD) did not differ by irradiation status. Age-related changes in relative volumes in controls reflected normal trends in humans with increasing WM and decreasing gray matter (GM) until middle age. Cerebrospinal fluid (CSF) volume did not differ across age in controls. WM volume was lower and CSF volume was higher in young, irradiated macaques. WM volume was similar between groups and CSF volume reduced in older irradiated macaques. GM volume was unaffected by radiation. TBI results in delayed WM expansion and long-term disruption of WM integrity. Diffusion changes suggest that myelin injury in WM is a hallmark of late-delayed radiation induced brain injury.

QOL-23. BASELINE TOTAL BRAIN VOLUME PREDICTS FOR POORER QOL AND REDUCED OVERALL SURVIVAL AFTER CRANIAL RADIOTHERAPY IN OLDER PATIENTS WITH GLIOBLASTOMA (GBM): RESULTS FROM THE PROSPECTIVE BRITER STUDY

Abstract GBM incidence peaks in the 7th and 8th decades of life with prognosis worsening with age. Short-course partial brain radiotherapy, +/- chemotherapy, extends survival but there is no validated evidence for prediction of individual risk of acute radiotherapy related side effects. BRITER, a prospective multicentre observational trial, recruited patients with newly diagnosed GBM aged ≥ 65 planned for cranial radiotherapy. Baseline MRI scans were analysed for 5 putative markers of brain resilience including relative total brain volume (ratio of cerebrospinal fluid (CSF) volume to total intracranial volume (TIV)) and their relationship to change in QoL. 126 patients were enrolled; mean age 72 years (range 65-83); 67% men, 33% women. 4% had a radiological diagnosis, 19% biopsy and 77% had debulking surgery. 21% received palliative radiotherapy alone (25% 30Gy/6#, 75% 40Gy/15#), 79% received radiotherapy with concurrent TMZ (47% 40Gy/15#, 53% 60Gy/30#). Median OS was 11.3 months. After accounting for age, sex, treatment and baseline MoCA score, there was a significant relationship between baseline CSF:TIV ratio and change in QoL score at 8 weeks post treatment. For each unit point of increase in CSF:TIV ratio, there was a corresponding decrease in EORTC QLC C30 QoL score by a factor of 1.27 (coefficient -1.27, 95% CI -3.24 to -0.19 p = 0.02). 35 participants were too unwell to complete questionnaires or had died by the 8 week follow up visit. In this subgroup, post hoc logistic regression showed baseline CSF:TIV ratio was related to risk of non-attendance (OR 1.35, 95% CI 1.01-1.80, p = 0.04). Cox regression models were fitted for time to death in 88 participants who had analysable baseline MRI sequences. Baseline CSF:TIV was associated with worsened OS (HR 1.41, 95% CI 1.19-1.66, p &amp;lt; 0.001). This unique prospective study indicates that baseline imaging parameters can predict the impact of cranial radiotherapy on QoL and OS.

BIOM-63. PROTEOMIC BASED PROFILING OF CSF FOR CNSL MANAGEMENT

Abstract Central nervous system lymphoma (CNSL) is a rare subtype of non-Hodgkin lymphoma, primarily affecting the brain and spinal cord. CNSL exhibits a dismal prognosis, as reflected by a low 5-year survival rate of 30%, with the current standard of care. The advent of multi-agent intrathecal chemotherapy (MAITC) in conjunction with systemic therapy has demonstrated encouraging outcomes, enhancing both progression-free survival and overall survival in patients with CNSL. Given the potential morbidity associated with MAITC, identification of minimally-invasive biomarkers for guiding patient management are necessary. Leveraging the longitudinal, large volume of Cerebrospinal fluid (CSF) afforded through our MAITC program, the objective of this study is to identify CSF-based proteomic biomarkers that can serve as reliable indicators of MAITC treatment response and CNSL management. Patient-matched CSF samples from the Penn State Health Neuroscience biorepository were banked at pre- and post-therapeutic endpoint in 22 primary and 36 secondary CNSL patients. The samples were profiled using high-throughput fluid sample protocol coupled with mass-spectrometry that only requires 30 μl of CSF. More than 1000 unique proteins were detected using shotgun proteomics, and 797 proteins were present in 70% of the analyzed samples, which were used for downstream analysis. We were able to effectively discriminate between primary and secondary CNSL based on protein abundance. Furthermore, the findings suggest significant changes in the cellular processes related to glycoprotein metabolism and redox signalling in response to the treatment, indicating a potential impact on protein modification and the cellular response to oxidative stress. Our comprehensive, pathway-level analysis uncovered significant molecular alterations, shedding light on their potential prognostic significance in the context of CNS lymphoma. Future work is underway to identify biomarker signatures that would predict optimal response to MAITC therapy, exhibiting potential to improve clinical decision making.

BIOM-65. NEW BIOMARKERS FOR THE DIAGNOSIS OF PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA IN CEREBROSPINAL FLUID: AN EXPLORATORY MULTICENTER RETROSPECTIVE COHORT STUDY

Abstract BACKGROUND Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin lymphoma which may be treated with curative intent. Diagnosis often requires a brain biopsy, which is associated with complications and delay of diagnosis. Cerebrospinal fluid (CSF) analysis can currently provide a diagnosis (without the need for a biopsy) in only a minority of PCNSL patients. The aim of this study is to identify new potential biomarkers in CSF for patients with clinical suspicion of PCNSL, to improve the diagnostic yield of CSF analysis. METHODS CSF samples were analyzed from a retrospective cohort that included patients with clinical suspicion of PCNSL at two Dutch hospitals between August 2020 and October 2021. First-step analysis consisted of targeted multiplex biomarker analysis using a proximity extension assay (Olink), allowing the simultaneous analysis (relative expression levels) of 184 protein markers in a small CSF volume. To validate the discovered biomarkers in a quantitative manner, a second analysis was performed in a subgroup of patients with a bead-based multiplex immune-assay (Luminex). RESULTS A total of 76 patients were included, of whom 11 patients (14%) were diagnosed with PCNSL. The mean age was 62 years (range 22-83 years), and 62% of the patients were male. In the primary analysis, 31 markers showed significant differences (p&amp;lt; 0.05) between PCNSL patients and controls. After correction for multiple testing, 6 markers remained significant, including the known chemokine marker CXCL13, as well as new markers. The quantitative analysis confirmed significant differences (p&amp;lt; 0.05) for 3 markers: CXCL10, programmed cell death protein 1 (PDCD1) and FAS natural ligand (FASLG). CONCLUSION We identified a novel panel of potential diagnostic markers in CSF for the diagnosis of PCNSL. The diagnostic value of these markers will be validated in an ongoing multicenter prospective study.

Abstract 16099: Life’s Essential 8 and Genetic Predisposition Predict Brain Volume Change, Mild Cognitive Impairment and Dementia Risk

Introduction: Life’s Essential 8 (LE8) are the key measures for improving and maintaining cardiovascular health, as defined by the American Heart Association in 2022. The associations of LE8 with future brain volume change, mild cognitive decline (MCI), and dementia have been unclear. Hypothesis: We hypothesized that LE8 status might be related to future brain volume change, and predict risk of MCI and all-cause dementia. Apolipoprotein E (APOE) gene and polygenic risk score (PRS) may modify the association between them. Methods: We used cohort data from UK Biobank. LE8 was categorized into low (&lt;50 score), moderate (50-79 score), and high (≥80 score) levels. Genetic predisposition was measured by APOE e4 carrier status and a polygenic risk score (PRS) calculated based on 39 non-APOE genetic variants. Linear regression models were used to analyze LE8 every 10-score increase and change of brain volume (total and hippocampus etc.). Cox regression models were used to estimate the hazard ratio (HR) and 95%CI on the association between LE8 and MCI and dementia. Results: We included 126,785 participants with a mean (SD) age of 56.0 (8.0) years and 53.5% were female. After a median of 13.0 years follow-up, we recorded 1797 (1.4%) people with MCI, and 1055 (0.8%) with dementia. Every 10-score increase of LE8 was related to 2826.11mm 3 increase in total brain volume, 8.41 and 12.04 mm 3 increase in left and right hippocampus volume respectively, while 393.41mm 3 decrease in ventricular cerebrospinal fluid volume (p values all &lt;0.001). Compared to people with a low LE8, those with a high LE8 were associated with decreased risk of MCI (HR 0.54, 95% CI 0.44-0.68) and dementia (0.63, 0.47-0.85). Compared to people with high LE8 and no APOE e4 allele, those with low LE8 and one or two APOE e4 alleles were associated with increased risk of MCI (2.36, 1.69-3.29) and dementia (4.37, 2.86-6.68). The joint effects of LE8 and PRS showed that people with high LE8 and low PRS had lower risk of dementia. Conclusions: High LE8 was associated with increased total brain volume, hippocampus volume and decreased ventricular cerebrospinal fluid volume. Higher LE8 was also linked to reduced risk of MCI and dementia. There were joint effects between LE8 and APOE, PRS on MCI and dementia risk.

Mapping the neuroanatomical abnormalities in a phenotype of male compulsive rats

Compulsivity is considered a transdiagnostic dimension in obsessive–compulsive and related disorders, characterized by heterogeneous cognitive and behavioral phenotypes associated with abnormalities in cortico-striatal-thalamic-cortical circuitry. The present study investigated the structural morphology of white and gray matter in rats selected for low- (LD) and high- (HD) compulsive drinking behavior on a schedule-induced polydipsia (SIP) task. Regional brain morphology was assessed using ex-vivo high-resolution magnetic resonance imaging (MRI). Voxel-based morphometry of segmented MRI images revealed larger white matter volumes in anterior commissure and corpus callosum of HD rats compared with LD rats. HD rats also showed significantly larger regional volumes of dorsolateral orbitofrontal cortex, striatum, amygdala, hippocampus, midbrain, sub-thalamic nucleus, and cerebellum. By contrast, the medial prefrontal cortex was significantly smaller in HD rats compared with LD rats with no significant group differences in whole brain, ventricular, or cerebrospinal fluid volumes. These findings show that limbic cortico-basal ganglia structures implicated in impulse control disorders are distinct in rats that are vulnerable to develop compulsive behavior. Such abnormalities may be relevant to the etiology of compulsive disorders in humans.

Practical aspects of the use of intrathecal chemotherapy

IntroductionIntrathecal chemotherapy is frequently used in clinical practice for treatment and prevention of neoplastic meningitis. Despite its widespread use, there is little information about practical aspects such as the volume of drug to be administered or its preparation and administration. ObjectiveTo conduct a literature review about practical aspects of the use of intrathecal chemotherapy. MaterialsSearch in PubMed/ Medline using the terms „chemotherapy AND intrathecal“, analysis of secondary and tertiary information sources. ResultsThe most widely used drugs in intrathecal therapy are methotrexate and cytarabine, at variable doses. One of the aspects with higher variability among different studies is their potential combination with a glucocorticoid, the specific corticoid selected and its dose. The efficacy and toxicity of the different combinations have not been compared. Regarding preparation, it is worth highlighting the recommendation to adjust pH and osmolarity to the physiological range, with the aim of improving tolerability. The volume of administration can influence distribution, and recommendated range is between 5 and 12 mL. Overall, it is recommended to extract a similar volume of cerebrospinal fluid before administration. The position of the patient during and after administration can have an impact on distribution and toxicity; lateral decubitus or sitting position is recommended in the first case, and prone and/ or supine position in the second one. Most publications don't explain how the treatment has been prepared or administered, and the lack of standardization could affect results. ConclusionsThere is a great variability in practice when using intrathecal chemotherapy, despite being an effective therapy, accepted by all international groups. This uncertainty is not li-mited to the drugs and doses administered, but it also includes the manner of preparation and the administration technique. The heterogeneity In clinical practice can Influence the efficacy and toxicity of this therapy.

Comparison of two corticosteroid regimens on brain volumetrics in patients with Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a neuromuscular disorder in which many patients also have neurobehavioral problems. Corticosteroids, the primary pharmacological treatment for DMD, have been shown to affect brain morphology in other conditions, but data in DMD are lacking. This study aimed to investigate the impact of two corticosteroid regimens on brain volumetrics in DMD using magnetic resonance imaging (MRI). In a cross-sectional, two-center study, T1-weighted MRI scans were obtained from three age-matched groups (9-18 years): DMD patients treated daily with deflazacort (DMDd, n = 20, scan site: Leuven), DMD patients treated intermittently with prednisone (DMDi, n = 20, scan site: Leiden), and healthy controls (n = 40, both scan sites). FSL was used to perform voxel-based morphometry analyses and to calculate intracranial, total brain, gray matter, white matter, and cerebrospinal fluid volumes. A MANCOVA was employed to compare global volumetrics between groups, with site as covariate. Both patient groups displayed regional differences in gray matter volumes compared to the control group. The DMDd group showed a wider extent of brain regions affected and a greater difference overall. This was substantiated by the global volume quantification: the DMDd group, but not the DMDi group, showed significant differences in gray matter, white matter, and cerebrospinal fluid volumes compared to the control group, after correction for intracranial volume. Volumetric differences in the brain are considered part of the DMD phenotype. This study suggests an additional impact of corticosteroid treatment showing a contrast between pronounced alterations seen in patients receiving daily corticosteroid treatment and more subtle differences in those treated intermittently.

Validation of targeted next-generation sequencing of cell-free DNA from archival cerebrospinal fluid specimens for the detection of somatic variants in cancer involving the leptomeninges: Cytopathologic and radiographic correlation.

Leptomeningeal metastases occur across multiple solid and lymphoid cancers, and patients typically undergo cytopathologic assessment of cerebrospinal fluid (CSF) in this setting. For patients diagnosed with metastatic cancer, the detection of actionable somatic mutations in CSF can provide clinically valuable information for treatment without the need for additional tissue collection. The authors validated a targeted next-generation sequencing assay for the detection of somatic variants in cancer (OncoPanel) on cell-free DNA (cfDNA) isolated from archival CSF specimens in a cohort of 25 patients who had undergone molecular testing of a prior tumor specimen. CSF storage time and volume had no impact on cfDNA concentration or mean target coverage of the assay. Previously identified somatic variants in CSF cfDNA were detected in 88%, 50%, and 27% of specimens diagnosed cytologically as positive, suspicious/atypical, and negative for malignancy, respectively. Somatic variants were identified in 81% of CSF specimens from patients who had leptomeningeal enhancement on magnetic resonance imaging compared with 31% from patients without such enhancement. These data highlight the stability of cfDNA in CSF, which allows for cytopathologic evaluation before triage for next-generation sequencing assays. For a subset of cases in which clinical suspicion is high but cytologic or radiographic studies are inconclusive, the detection of pathogenic somatic variants in CSF cfDNA may aid in the diagnosis of leptomeningeal metastases.

Causal Associations of Genetically Determined Tinnitus With Neuroimaging Traits: Evidence From a Mendelian Randomization Study.

Potential reverse causality and unmeasured confounding factors are common biases in most neuroimaging studies on tinnitus and central correlates. The causal association of tinnitus with neuroimaging features also remains unclear. This study aimed to investigate the causal relationship of tinnitus with neuroplastic alterations using Mendelian randomization. Summary-level data from a genome-wide association study of tinnitus were derived from UK Biobank (n = 117,882). The genome-wide association study summary statistics for 4 global-brain tissue and 14 sub-brain gray matter volumetric traits were also obtained (n = up to 33,224). A bidirectional Mendelian randomization analysis was conducted to explore the causal relationship between tinnitus and neuroanatomical features at global-brain and sub-brain levels. Genetic susceptibility to tinnitus was causally associated with increased white matter volume (odds ratio [OR] = 2.361, 95% confidence interval [CI], 1.033 to 5.393) and total brain volume (OR = 2.391, 95% CI, 1.047 to 5.463) but inversely associated with cerebrospinal fluid volume (OR = 0.362, 95% CI, 0.158 to 0.826). A smaller gray matter volume in the left Heschl's gyrus and right insular cortex and larger gray matter volume in the posterior division of the left parahippocampal gyrus may lead to an increased risk for tinnitus (OR = 0.978, 95% CI, 0.961 to 0.996; OR = 0.987, 95% CI, 0.976 to 0.998; and OR = 1.015, 95% CI, 1.001 to 1.028, respectively). Genetic susceptibility to tinnitus was causally associated with increased white matter volume and total brain volume. Volume alteration in several cortical regions may indicate a higher tinnitus risk, and further research is recommended for causality inference at the level of sub-brain regions. Our findings provide genetic evidence for elucidating the underlying pathophysiological mechanisms of tinnitus-related neuroanatomical abnormalities.