Baseline CSF Research Articles

The combination of CSF neurofilament light chain and glial fibrillary acidic protein improves the prediction of long-term confirmed disability worsening in multiple sclerosis

Our objective was to evaluate the individual and combined prognostic attributes of baseline serum and CSF measurements of Neurofilament light chain (sNfL, cNfL) and glial fibrillary acidic protein (sGFAP, cGFAP) on long term clinical outcomes in MS. In this retrospective single center study, patients with serum and CSF stored at first MS presentation and > 15-years of follow-up were analyzed. NfL and GFAP were quantified from cryopreserved samples using a digital immunoassay and analyzed as predictors of confirmed disability worsening (CDW). Sixty patients (70% female) underwent baseline tandem CSF and serum sampling and were followed for a mean of 17.8 years (SD 2.5). 32 developed CDW. By logistic regression, while sNfL cNfL and cGFAP showed prognostic merit (AUC 0.72, 0.70, 0.62 respectively), sGFAP did not (AUC 0.5). The combination of cNfL and cGFAP improved CDW prediction compared to either measure considered in isolation (AUC 0.72). The optimal predictive cut-off for CDW (Youden’s index) for cNfL was 596 pg/mL and for cGFAP was 8160 pg/mL. Kaplan–Meier analysis of the cutoff-defined ‘high-high’ and ‘low-low’ combined cNfL and cGFAP groupings improved prediction of CDW compared to either marker individually (Hazard ratio 4.5 (95% CI 2.7–18.3), Logrank P < 0.0001). Cox Proportional Hazards regression demonstrated that high baseline cNfL and cGFAP were independently prognostic of subsequent CDW after adjusting for baseline age, sex, EDSS score and subsequent treatment exposure. Each unit increase in Ln(cNfL) and Ln(cGFAP) was respectively associated with an additional hazard of 2.36 (95% CI 1.12–5.52) and 2.26 (95% CI 1.03–5.21). CSF NfL and GFAP are independently prognostic of long-term clinical worsening in MS, and may represent a complementary pairing.

Anti-Hypertensives Reduce the Rate of Alzheimer’s Disease Progression: A Cohort Study Linked with Genetic and Neuropathological Analyses

BackgroundArterial hypertension contributes to both the development and progression of dementia due to both Alzheimer’s disease (A.D.) and vascular pathology. However, the effects of different classes of anti-hypertensives (A.H.T.s), on the rate of dementia progression and brain neuropathology are unknown.ObjectiveTo investigate the effect of each class of A.H.T., both as single and combined, on the rate of dementia progression. In addition, we analyzed the effect of A.H.T.s on brain neuropathology in AD participants, indicated by Braak staging, hippocampal atrophy, and baseline CSF levels of A-β42, total (T) tau, and P-181 tau.MethodsWe have used the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS).ResultsA.H.T.s were associated with reduced yearly increase in the CDR-SOB scores of 1.025 during a 10-year follow-up (P<0.001). The overall survival rate was higher in A.H.T. users than non-users [HR: 0.912: 0.860, 0.967) P=0.002]. These trends continued when stratifying participants by age, gender, and APOE4 allele. Participants who did not use A.H.T.s had a mean yearly increase of 1.71±1.7 in the CDR-SOB scores. This value was reduced to 1.48±1.6, P=0.006 and 1.45±1.6, P=0.024 for participants with documented use of βB and A.R.B.s, respectively. Combining diuretics with α1-AB or ACEI led to synergistic effects in reducing the rise in CDR-SOB scores. The proportion of participants who were diagnosed having AD postmortem with severe Braak staging was significantly lower in A.H.T.-users than non-users. The severity of Braak staging, and hippocampal atrophy differed in participants >70 vs. <70 years old, in both males and females. A significant relationship was observed between hippocampal atrophy and Braak staging; and between hippocampal atrophy and baseline CSF levels of P-181 tau.ConclusionOur results could have implications for halting the progression of dementia regardless of the etiology being related to AD or vascular pathology. The choice of combination of A.H.T. therapy should also consider the combination which would lead to an optimum benefit in slowing the progression of dementia. Additionally, our results underline a more complex A.D. disease model than previously thought, which opens new treatment options.

Prognostic Value of CSF IL-10 at Early Assessment of Induction Chemotherapy in Primary CNS Lymphomas: A LOC Network Study.

Despite a high response rate at the first evaluation during induction chemotherapy, the risk of early relapse remains high and unpredictable in primary CNS lymphomas (PCSNLs). We aimed to assess the prognostic value of early IL-10 levels in CSF (e-IL-10) after 2 months of induction chemotherapy. We retrospectively selected from the LOC (Lymphomes Oculo-Cérébraux) network database patients with PCSNLs who had complete or partial response at the 2-month evaluation of a high-dose methotrexate-based first-line chemotherapy for whom e-IL-10 was available. Thirty patients (median age: 62 years, brain involvement in 30/30, CSF involvement in 10/30, median baseline CSF IL-10: 27.5 pg/mL) met the selection criteria. e-IL-10 was undetectable in 22 patients and detectable in 8 patients. At the end of induction treatment, 7 of 8 and 4 of 22 of the patients with detectable and undetectable e-IL-10 had experienced progressive disease, respectively (p = 0.001, OR: 26.8, 95% CI 2-1,478). The median progression-free survival times were 5.8 months (95% CI 2.8-8.8) and 28.7 months (95% CI 13.4-43.9) in the groups with detectable and undetectable e-IL-10, respectively (p < 0.001). Our results suggest that despite an objective response, the persistence of detectable e-IL-10 is associated with a high risk of early relapse in PCNSL. A closer follow-up of such patients is warranted.

Cerebrospinal fluid biomarkers and cognitive trajectories in patients with Alzheimer’s disease and a history of traumatic brain injury

Traumatic brain injury (TBI) and Alzheimer’s disease (AD) have overlapping mechanisms but it remains unknown if pathophysiological characteristics and cognitive trajectories in AD patients are influenced by TBI history. Here, we studied AD patients (stage MCI or dementia) with TBI history (ADTBI+, n=110), or without (ADTBI-, n=110) and compared baseline CSF concentrations of amyloid beta 1–42 (Aβ42), phosphorylated tau181 (pTau181), total tau, neurofilament light chain (NfL), synaptosomal associated protein-25kDa (SNAP25), neurogranin (Ng), neuronal pentraxin-2 (NPTX2) and glutamate receptor-4 (GluR4), as well as differences in cognitive trajectories using linear mixed models. Explorative, analyses were repeated within stratified TBI groups by TBI characteristics (timing, severity, number). We found no differences in baseline CSF biomarker concentrations nor in cognitive trajectories between ADTBI+ and ADTBI- patients. TBI >5 years ago was associated with higher NPTX2 and a tendency for higher SNAP25 concentrations compared to TBI ≤ 5 years ago, suggesting that TBI may be associated with long-term synaptic dysfunction only when occurring before onset or in a pre-clinical disease stage of AD.

Longitudinal Relationship Between Brain Atrophy Patterns, Cognitive Decline, and Cerebrospinal Fluid Biomarkers in Alzheimer's Disease Explored by Orthonormal Projective Non-Negative Matrix Factorization.

Longitudinal magnetic resonance imaging (MRI) has been proposed for tracking the progression of Alzheimer's disease (AD) through the assessment of brain atrophy. Detection of brain atrophy patterns in patients with AD as the longitudinal disease tracker. We used a refined version of orthonormal projective non-negative matrix factorization (OPNMF) to identify six distinct spatial components of voxel-wise volume loss in the brains of 83 subjects with AD from the ADNI3 cohort relative to healthy young controls from the ABIDE study. We extracted non-negative coefficients representing subject-specific quantitative measures of regional atrophy. Coefficients of brain atrophy were compared to subjects with mild cognitive impairment and controls, to investigate the cross-sectional and longitudinal associations between AD biomarkers and regional atrophy severity in different groups. We further validated our results in an independent dataset from ADNI2. The six non-overlapping atrophy components represent symmetric gray matter volume loss primarily in frontal, temporal, parietal and cerebellar regions. Atrophy in these regions was highly correlated with cognition both cross-sectionally and longitudinally, with medial temporal atrophy showing the strongest correlations. Subjects with elevated CSF levels of TAU and PTAU and lower baseline CSF Aβ42 values, demonstrated a tendency toward a more rapid increase of atrophy. The present study has applied a transferable method to characterize the imaging changes associated with AD through six spatially distinct atrophy components and correlated these atrophy patterns with cognitive changes and CSF biomarkers cross-sectionally and longitudinally, which may help us better understand the underlying pathology of AD.

Neuropsychiatric Symptoms and In Vivo Alzheimer's Biomarkers in Mild Cognitive Impairment.

Neuropsychiatric symptoms (NPS) carry an increased risk of progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD). There is a need to understand how to integrate NPS into the paradigm outlined in the 2018 NIA-AA Research Framework. To evaluate a prediction model of MCI-AD progression using a collection of variables, including NPS, cognitive testing, apolipoprotein E4 status (APOE4), imaging and laboratory AD biomarkers. Of 300 elderly subjects, 219 had stable MCI and 81 MCI-AD progression over a 5-year follow-up. NPS were measured using the Neuropsychiatric Inventory (NPI). A multivariate Cox Proportional Hazards Regression Analysis assessed the effects of APOE4, baseline NPI, baseline CSF amyloid-β, phosphorylated and total tau, baseline AD-signature MRI biomarker, baseline memory and executive function on MCI-AD progression. 27% progressed to dementia (median follow-up = 43 months). NPS were found in stable MCI (62.6%) and MCI-AD converters (70.3%). The Cox model exhibited a good fit (p < 0.001), and NPS (HR = 1.033, p = 0.027), phosphorylated tau (HR = 1.011, p = 0.025), total tau (HR = 1.005, p = 0.024), AD-signature MRI biomarker (HR = 0.111, p = 0.002), executive function (HR = 0.727, p = 0.045), and memory performance (HR = 0.387, p < 0.001) were significantly associated with dementia. NPS may inform dementia risk assessment in conjunction with cognitive testing and imaging and laboratory AD biomarkers. NPS is independently associated with the risk of MCI-dementia progression, over and beyond the contributions of CSF biomarkers.

Higher baseline cerebrospinal fluid platelet‐derived growth factor receptor‐β levels are associated with slower reductions in longitudinal cerebral blood flow among cognitively unimpaired individuals

AbstractBackgroundCerebrospinal fluid (CSF) platelet‐derived growth factor receptor‐β (PDGFR‐β) is an emerging biomarker hypothesized to reflect pericyte damage. CSF PDGFR‐β levels are increased in Alzheimer’s disease (AD), but it is unknown if pericyte injury contributes to cerebrovascular changes common in AD. We examined if PDGFR‐β relates to changes in cerebral blood flow (CBF) and white matter injury in older adults.MethodVanderbilt Memory and Aging Project participants (n = 152, baseline age 73±7 years, 43% mild cognitive impairment [MCI]) underwent baseline lumbar puncture and serial brain MRI over a 7‐year (5.5±2.3) follow‐up period. CSF PDGFR‐β concentrated was measured by immunoassay. MRI included pseudo‐continuous arterial spin‐labeling to quantify CBF, T2‐FLAIR to quantify white matter hyperintensities (WMHs), and diffusion tensor imaging (DTI) to quantify white matter microstructural integrity. Ordinary least squares regression and linear mixed‐effects models related baseline CSF PDGFR‐β to baseline and longitudinal whole brain and regional CBF, WMH, and DTI metrics, adjusting for baseline demographic variables, modified Framingham Stroke Risk Profile, cognitive status, apolipoprotein‐ε4 status, and regional tissue volume. Longitudinal models adjusted for follow‐up time. Follow‐up models tested a CSF PDGFR‐β x cognitive status interaction.ResultIn main models, higher CSF PDGFR‐β levels were cross‐sectionally associated with lower mean diffusivity (indicating better microstructural integrity) in white matter tracts in the frontal, temporal, parietal, and occipital lobes (p‐values&lt;0.03) but were unrelated to WMHs (p‐values&gt;0.18). Models investigating associations with longitudinal white matter variables were null (p‐values&gt;0.35). CSF PDGFR‐β cross‐sectionally interacted with diagnosis on temporal lobe CBF, such that higher CSF PDGFR‐β related to higher CBF in MCI participants (p = 0.01). In longitudinal models, baseline CSF PDGFR‐β interacted with cognitive status on whole brain and occipital lobe CBF (p‐values&lt;0.04). Stratified models showed higher baseline CSF PDGFR‐β related slower reductions in longitudinal CBF in whole brain (p = 0.02), frontal (p = 0.04), temporal (p = 0.02), parietal (p = 0.01), and occipital lobes (p = 0.008) in cognitively unimpaired participants only.ConclusionAmong older adults, higher CSF PDGFR‐β levels are associated with better white matter integrity at study entry and predict slower reductions in longitudinal CBF among cognitively unimpaired individuals. Results suggest that higher PDGFR‐β levels may reflect subclinical vascular remodeling that provides protection to future cerebrovascular compromise.

Minor neuropsychological deficits in SCD: Association with AD biomarkers and cognitive decline

AbstractBackgroundThe clinical relevance and longitudinal impact of minor neuropsychological deficits (MND) in cognitively normal memory clinic patients with subjective cognitive decline (SCD) is still unclear. To address this, we set out to investigate whether MND in SCD patients are related to Alzheimer´s disease (AD) pathology and future cognitive decline. In addition, we wanted to assess whether SCD patients have an increased risk of neuropathology and cognitive decline even in the absence of MND.MethodWe included 233 cognitively normal, healthy control participants (HC) without subjective cognitive concerns and 439 memory clinic SCD patients with available baseline CSF and/or longitudinal cognitive data from the observational DZNE Longitudinal Cognitive Impairment and Dementia (DELCODE) study. Participants, who scored at least 0.5SD below the mean on a composite measure calculated from the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuropsychological assessment battery, were classified as having MND. We compared the resulting participant groups regarding their baseline CSF Aβ42/40, p‐tau181, t‐tau and Aβ42/p‐tau181 levels, longitudinal preclinical Alzheimer´s cognitive composite (PACC5) trajectories and risk of progression to incident mild cognitive impairment (MCI).ResultCompared to SCD patients without MND (n = 384), SCD patients with MND (n = 55, 12.5% of SCD sample) showed significantly elevated CSF AD biomarker levels, accelerated PACC5 decline and a higher risk of progression to incident MCI. Baseline MND had a positive predictive value of 57.0% (95%CI: 38.5‐75.4) and a negative predictive value of 86.0% (95%CI: 81.9‐90.1) for the progression to incident MCI within 3 years. SCD patients without MND showed increased PACC5 decline and a higher risk of incident MCI compared to HC participants without MND (n = 215), but did not differ from HC participants in their CSF biomarker levels.ConclusionMND are a risk factor for AD pathology and cognitive decline in memory clinic patients with SCD. The assessment of MND could thus provide useful information for AD risk stratification and enrichment in SCD samples. Importantly, SCD patients still have an increased risk for cognitive decline in the absence of MND.

Longitudinal trajectories of myelin loss in the context of Alzhiemer’s disease biomarkers, glial activation, and APOE4

AbstractBackgroundLower measures of myelin have been associated with abnormal levels of AD biomarkers and APOE4 carriage. However, most human studies have been cross‐sectional, leaving the relationship between AD and myelin changes unclear. The purpose of this study was to determine the association between AD pathology, APOE4, glial activation, and longitudinal changes in quantitative R1 (qR1), a marker sensitive to myelination obtained via MPnRAGE MRI.MethodParticipants from the Wisconsin Registry for Alzheimer’s Prevention (WRAP) and Wisconsin Alzheimer’s Disease Research Center (ADRC) were selected based on available longitudinal MPnRAGE, clinical diagnosis, and APOE genotyping (N = 446). A subset (N = 141) included those with available baseline CSF (AB42/40, pTau181), and gliosis markers (sTREM2, GFAP, YKL40) measured using a robust prototype assay as part of the Roche NeuroToolKit research platform (Roche International). Longitudinal mean qR1 was estimated from white matter regions from the ICBM‐DTI‐81 atlas. In the overall sample, linear mixed effects models predicting regional qR1 (FDR‐corrected) with random intercepts and slopes were estimated controlling for sex, age centered within‐subjects (agec), age averaged within‐subjects (agegm), cognitive impairment, and APOE4 carriage as covariates. Two‐way interactions between impairment and APOE4 with agec were tested in the overall sample as were moderating effects of CSF amyloid‐positivity, pTau181, and gliosis markers on agec in the CSF sample.ResultIn the overall sample, older agec, agegm, and female sex were associated with lower qR1 in a majority of tracts indicating substantial longitudinal declines in qR1 over time and lower qR1 with advanced age and female sex. Sex, impairment, and APOE4 did not show significant agec interactions. Likewise, none of the CSF biomarkers moderated the effect of agec in the CSF subsample.ConclusionWhile aging is robustly associated with longitudinal demyelination as potentially indexed by qR1, these rates do not appear to be moderated by AD pathology, cognitive impairment, APOE4, or glial activation in early disease. Given the capacity for re‐myelination in the context of injury, longitudinal studies are critical for parsing myelin and AD relationships. Established associations between myelin and AD risk may reflect later disease processes, particularly in samples more enriched for tau pathology.

Detecting cortical microstructural alterations secondary to white matter hyperintensity in amyloid positive cognitively normal subjects

AbstractBackgroundPrevious research showed that cortical diffusivity is sensitive to primary cortical microstructural changes due to amyloid deposition (1). The present study aimed to investigate the cortical microstructural alterations secondary to white matter damage in cognitively normal participants, amyloid positive and negative.MethodThree hundred and thirty‐five cognitively normal (MMSE &gt; 24) participants with baseline CSF Aß42 and MRI scans were obtained from the European Prevention of Alzheimer’s Dementia (EPAD) cohort. Participants were classified as Aß42‐ (N = 231) or Aß42+ (N = 104), based on a published cut‐off (2). The Fazekas scale deep white matter (FSDWM) score was used to further classify participants as LOW (0 and 1; N = 281) or HIGH (2 and 3; N = 54) FSDWM. Structural and diffusion MRI (dMRI) were used to calculate whole brain cortical volume fraction, cortical thickness and three neuropathology‐inspired cortical diffusivity measures: the angle between the radial minicolumnar direction and the principal diffusion direction (AngleR); the principal diffusion component parallel with the minicolumns (ParlPD), and the diffusion components perpendicular to the minicolumns (PerpPD+). Group differences in structural and diffusion metrics were tested using GLM adjusting for scanner manufacturer, number of dMRI volumes, age and sex, with Bonferroni’s correction (p&lt;0.05/5).ResultThe interaction between Aß42 status and FSDWM revealed significant differences in cortical microstructural measures (GLM: AngleR F17,317 = 7.065, p = 0.008; PerpPD+ F17,317 = 7.976, p = 0.005). The pairwise comparisons showed significantly lower AngleR values in Aß42‐ HIGH compared to Aß42‐ LOW and significantly higher PerpPD+ values in Aß42+ HIGH compared to Aß42+ LOW (Figure). No significant differences in structural measures (thickness or volume) were detected.ConclusionCortical diffusivity measures can detect differences in cortical microstructure of amyloid positive and negative participants with different WM damage severity. The reduced AngleR value in Aß42‐ HIGH participants was potentially due to neuroinflammatory processes, consistent with previous findings(1). The higher PerpPD+ values in Aß42+ HIGH may indicate the secondary cortical microstructural damage.

A novel approach to measure dyadic patterns of subjective cognitive changes: its association to Alzheimer’s disease biomarkers and ability to predict clinical progression in cognitively normal older adults

AbstractBackgroundDiscrepancy in the dyadic relationship of subjective cognitive change has revealed both increased/heightened awareness and decreased awareness/unawareness in the predementia stages of Alzheimer’s Disease (AD). The dyadic relationship is often calculated using the mean discrepancy between an individual and their study partner’s scores on a memory complaints questionnaire. However, participants may display heightened awareness on some questions and unawareness on others, canceling out each other’s effect and masking subtle changes in either direction. Here, we present a new item‐level methodological approach allowing us to examine individual subtle changes in these two awareness dimensions separately. Moreover, we compared them to AD pathology and investigated their ability to predict clinical progression.MethodA total of 503 ADNI participants (Table.1) with baseline clinical dementia rating (CDR) = 0 and baseline CSF (Aβ1‐42 and t‐tau) were included. A subset (N = 329) had at least two follow‐up CDR time points to compute clinical progression. A traditional score was calculated as the average discrepancy between the partner and participant’s responses on the Everyday Cognition questionnaire, with positive scores indicating heightened awareness and negative scores indicating unawareness. An unawareness (resp., heightened awareness) sub‐score was computed by applying a ceiling (resp., floor) at zero to item‐level differences before averaging. Each measure was compared by AD pathology, adjusted for age and sex. Survival analyses examined the relationship of the new scores with clinical progression.ResultCSF t‐tau, but not Aβ1‐42, was a significant independent predictor of the traditional and unawareness scores in models adjusting for each other. There was no significant interaction between the two (Table.2). Survival analyses showed a one‐point improvement on the unawareness sub‐score associated with an 84% reduction in progression hazard (HR = 0.16, p&lt;0.001), or equivalently. A one‐point decline and 525% increase in progression hazard, with no significant effect for the heightened awareness score.ConclusionDecomposing the traditional awareness score into two sub‐scores, allowed the investigation of the relationship between AD and awareness with more specific, sensitive measures. Of these, the unawareness sub‐score was associated with t‐tau and a strong predictor of clinical progression, providing further support that discordant self‐ and informant‐reported cognitive decline may provide important clinical information.

Refinement of Neurofilament light Dynamics in CSF and Blood for familial Alzheimer’s Disease

AbstractBackgroundDisease‐modifying therapies for Alzheimer’s Disease (AD) are likely most beneficial when initiated in the pre‐symptomatic phase. To track success of such interventions fluid biomarkers became instrumental, with neurofilament light chain (NfL) showing particular promise. We previously reported that serum NfL increases in pre‐symptomatic phases of familial (autosomal‐dominantly inherited) AD (fAD) and that within‐person rate‐of‐change in NfL is an earlier predictor of fAD symptom onset compared to cross‐sectional levels. The aim of the study at hand was to extend these initial findings in a larger cohort.MethodParticipants enrolled in the Dominantly Inherited Alzheimer Network (DIAN) with matched cross‐sectional and longitudinal cerebrospinal fluid (CSF; n = 962) as well as plasma (n = 1294) samples were used. NfL measurements have been performed on the SIMOA platform using commercially available assay‐kits. To investigate the influence of physiological factors independent from AD, we first analyzed whether age and body mass index (BMI) could account for observed variation in inter‐individual CSF and plasma NfL levels considering non‐carrier family‐members (NC) as a healthy control group. Next, utilizing estimated years to symptom onset (EYO) and previously published methods (Preische et al., 2019), we determined the point in disease course when baseline and longitudinal CSF and plasma NfL concentrations started to increase in mutation carriers (MC) relative to NC, after adjusting for age and BMI.ResultOur results reveal a tight correlation of CSF and blood NfL values within MC as well as NC (figure 1A‐B). However, within NC, after correction for age and BMI, some unexplained variability remained (figure 1C). Further, a decrease of the NfL plasma/CSF ratio over age was found after correcting for BMI (figure 1D). The discrimination of MC from NC was equally good for plasma compared to CSF, being possible on the group level as early as around ‐15 to almost ‐20 EYO depending on the modelling (figure 2).ConclusionOur results support plasma equivalently to CSF NfL as a clinically useful biomarker to longitudinally track neurodegeneration in fAD. The systemic factors influencing physiological NfL values in blood should be investigated in future studies to further improve interpretation of this biomarker.

Late‐life hypertension acts together with amyloid‐β pathology to promote early cognitive decline

AbstractBackgroundMidlife hypertension (HTN) is a known risk factor for Alzheimer’s Disease (AD) development. However, whether the same effect is observed in older individuals, at risk for AD, remains to be elucidated. Here, we aimed to assess whether late‐life HTN and the presence of amyloid‐β pathology (Aβ) interact to promote longitudinal cognitive decline in cognitively unimpaired (CU) individuals, and if systolic blood pressure (SBP) levels moderate this interaction. Interactive effect of disease pathophysiology is crucial for dementia prevention strategies.MethodWe used two independent cohorts. We evaluated 475 CU individuals over 65 years of age from the ADNI cohort, with available baseline medical data and CSF Elecsys biomarkers (Aβ1‐42 and p‐tau181), as well as longitudinal clinical assessments with neuropsychological testing (up to 6 years); the individuals were classified as (A)+ or (A)‐ based on a previously proposed cut‐off of CSF p‐tau181/Aβ1‐42 lower than 0.025. We also evaluated 162 CU individuals over 65 years of age from the TRIAD cohort with baseline clinical data and Aβ‐PET, as well as longitudinal clinical assessments with neuropsychological testing (up to 3 years). The individuals were classified as (A)+ or (A)‐ based on Aβ‐PET positivity. All individuals were classified as positive or negative for hypertension based on medical history. For the ADNI cohort, we could also evaluate the SBP levels as a continuous variable.ResultLinear mixed‐effects (LME) models showed that HTN and Aβ acted together to promote longitudinal cognitive decline (ADNI: HTN X Aβ X Time, β = ‐0.44, p = 0.001, figure 1, TRIAD: HTN X Aβ X Time, β = ‐0.64, p &lt; 0.001, figure 2). Also, we could see that higher SBP levels acted together with Aβ to promote further cognitive decline (SBP values X Aβ X Time, β = ‐0.011, p = 0.03, figure 3).ConclusionOur results support a framework in which late‐life HTN is a modifiable risk factor for cognitive decline in CU individuals at increased risk for AD. This supports further investigation in determining the best target of SBP levels for individuals at risk for AD, in the context of offering precision medicine for this population.

Longitudinal white matter integrity alterations as a function of Preclinical Alzheimer’s Pathology: findings from the EPAD non‐demented cohort

AbstractBackgroundCross‐sectional diffusion tensor imaging (DTI) studies report white matter (WM) microstructural alterations, mainly involving fornix and corpus callosum (CC), in symptomatic stages of Alzheimer’s Disease (AD). Exploring these changes longitudinally in relation to preclinical and prodromal AD pathology is essential to track disease progression. We investigated trajectories of WM alterations in non‐demented individuals from the European Prevention of Alzheimer’s Dementia (EPAD) cohort and their relationship with AD biomarkers.MethodEPAD inclusion criteria were age&gt;50 years and Clinical Dementia Rating = 0.5. We selected participants with baseline CSF samples, and longitudinal DTI scans. After defining AT groups(Ingala et al. 2021), A‐T+ participants were excluded (final N = 283). MRI acquisition and preprocessing was previously described(Lorenzini et al. 2022). We extracted fractional anisotropy (FA) in 14 regions(Mori et al. 2005) from DTI as a marker of WM integrity. Site harmonization of MRI‐derived data was performed with ComBat toolbox(Fortin et al. 2018). Age‐ and sex‐corrected linear mixed models with random intercepts on participants were used to estimate time‐effect on MRI‐derived phenotypes, and their interaction with AT status. Results were corrected for multiple testing.ResultAt baseline, A+T‐ participants showed lower FA in body/columns (ß = ‐0.04, p&lt;0.01) and crus of fornix (ß = ‐0.01, p = 0.04), and in splenium (ß = ‐0.007, p = 0.04) and body of CC (ß = ‐0.01, p = 0.03) compared to A‐T‐. In the whole group, FA decreased over time in splenium (ß = ‐0.003, p&lt;0.01), body (ß = ‐0.002, p&lt;0.01) and genu of CC (ß = ‐0.009, p&lt;0.01), body/columns (ß = ‐0.004, p&lt;0.01) and crus of fornix (ß = ‐0.005, p&lt;0.01), and inferior longitudinal fasciculus (ß = ‐0.007, p&lt;0.01). Compared to A‐T‐, A+T+ participants showed steeper FA reduction in superior (Interaction:ß = ‐0.004, p = 0.03) and anterior corona radiata (Interaction:ß = ‐0.006, p = 0.02).ConclusionOur results suggest that WM integrity in key AD regions may degenerate early in the AD continuum, showing greater impairment over short‐time intervals in individuals with higher AD‐specific pathological burden.

Longitudinal white matter integrity alterations as a function of Preclinical Alzheimer’s Pathology: findings from the EPAD non‐demented cohort

AbstractBackgroundCross‐sectional diffusion tensor imaging (DTI) studies report white matter (WM) microstructural alterations, mainly involving fornix and corpus callosum (CC), in symptomatic stages of Alzheimer’s Disease (AD). Exploring these changes longitudinally in relation to preclinical and prodromal AD pathology is essential to track disease progression.We investigated trajectories of WM alterations in non‐demented individuals from the European Prevention of Alzheimer’s Dementia (EPAD) cohort and their relationship with AD biomarkers.MethodEPAD inclusion criteria were age&gt;50 years and Clinical Dementia Rating≤0.5. We selected participants with baseline CSF samples, and longitudinal DTI scans. After defining AT groups(Ingala et al. 2021), A‐T+ participants were excluded (final N = 283).MRI acquisition and preprocessing was previously described(Lorenzini et al. 2022). We extracted fractional anisotropy (FA) in 14 regions(Mori et al. 2005) from DTI as a marker of WM integrity. Site harmonization of MRI‐derived data was performed with ComBat toolbox(Fortin et al. 2018).Age‐ and sex‐corrected linear mixed models with random intercepts on participants were used to estimate time‐effect on MRI‐derived phenotypes, and their interaction with AT status. Results were corrected for multiple testing.ResultAt baseline, A+T‐ participants showed lower FA in body/columns (ß = ‐0.04, p&lt;0.01) and crus of fornix (ß = ‐0.01, p = 0.04), and in splenium (ß = ‐0.007, p = 0.04) and body of CC (ß = ‐0.01, p = 0.03) compared to A‐T‐. In the whole group, FA decreased over time in splenium (ß = ‐0.003, p&lt;0.01), body (ß = ‐0.002, p&lt;0.01) and genu of CC (ß = ‐0.009, p&lt;0.01), body/columns (ß = ‐0.004, p&lt;0.01) and crus of fornix (ß = ‐0.005, p&lt;0.01), and inferior longitudinal fasciculus (ß = ‐0.007, p&lt;0.01). Compared to A‐T‐, A+T+ participants showed steeper FA reduction in superior (Interaction:ß = ‐0.004, p = 0.03) and anterior corona radiata (Interaction:ß = ‐0.006, p = 0.02).ConclusionOur results suggest that WM integrity in key AD regions may degenerate early in the AD continuum, showing greater impairment over short‐time intervals in individuals with higher AD‐specific pathological burden.

Detecting cortical microstructural alterations secondary to white matter hyperintensity in amyloid positive cognitively normal subjects

AbstractBackgroundPrevious research showed that cortical diffusivity is sensitive to primary cortical microstructural changes due to amyloid deposition (1). The present study aimed to investigate the cortical microstructural alterations secondary to white matter damage in cognitively normal participants, amyloid positive and negative.MethodThree hundred and thirty‐five cognitively normal (MMSE &gt; 24) participants with baseline CSF Aβ42 and MRI scans were obtained from the European Prevention of Alzheimer’s Dementia (EPAD) cohort. Participants were classified as Aβ42‐ (N = 231) or Aβ42+ (N = 104), based on a published cut‐off (2). The Fazekas scale deep white matter (FSDWM) score was used to further classify participants as LOW (0 and 1; N = 281) or HIGH (2 and 3; N = 54) FSDWM.Structural and diffusion MRI (dMRI) were used to calculate whole brain cortical volume fraction, cortical thickness and three neuropathology‐inspired cortical diffusivity measures: the angle between the radial minicolumnar direction and the principal diffusion direction (AngleR); the principal diffusion component parallel with the minicolumns (ParlPD), and the diffusion components perpendicular to the minicolumns (PerpPD+).Group differences in structural and diffusion metrics were tested using GLM adjusting for scanner manufacturer, number of dMRI volumes, age and sex, with Bonferroni’s correction (p&lt;0.05/5).ResultThe interaction between Aβ42 status and FSDWM revealed significant differences in cortical microstructural measures (GLM: AngleR F17,317 = 7.065, p = 0.008; PerpPD+ F17,317 = 7.976, p = 0.005). The pairwise comparisons showed significantly lower AngleR values in Aβ42‐ HIGH compared to Aβ42‐ LOW and significantly higher PerpPD+ values in Aβ42+ HIGH compared to Aβ42+ LOW (Figure). No significant differences in structural measures (thickness or volume) were detected.ConclusionCortical diffusivity measures can detect differences in cortical microstructure of amyloid positive and negative participants with different WM damage severity. The reduced AngleR value in Aβ42‐ HIGH participants was potentially due to neuroinflammatory processes, consistent with previous findings(1). The higher PerpPD+ values in Aβ42+ HIGH may indicate the secondary cortical microstructural damage.

INNV-39. INVESTIGATING MULTI-AGENT INTRATHECAL CHEMOTHERAPY AS A TREATMENT FOR PRIMARY AND SECONDARY CENTRAL NERVOUS SYSTEM LYMPHOMA: SAFETY AND EFFICACY RESULTS FROM AN INSTITUTIONAL COHORT STUDY

Abstract INTRODUCTION Despite exquisite responses to initial therapy for CNS lymphoma, relapse is common and overall responses are disappointing compared to non-CNS diffuse large B-cell lymphomas. Literature reports 1 and 3 year survival rates of 50% and 30-40% respectively, with standard treatment. Intravenous, high-dose-methotrexate-based therapies have become the standard of care, with many variations but no consensus. Incorporation of multi-agent intrathecal chemotherapy (MAITC) alongside systemic therapy is novel but not widely adopted. We report our institutional data on safety and efficacy of MAITC in CNS lymphoma. METHODS A retrospective review of patients with primary or secondary CNS lymphoma, treated with MAITC between August 2015 and December 2021, was conducted. Each cycle includes alternating combinations of 2-3 of the following drugs: methotrexate, rituximab, cytarabine, etoposide, topotecan, gemcitabine, and thiotepa, via ommaya reservoir. Log-rank tests and Cox regression were used to evaluate survival differences. RESULTS 59 patients were reviewed (21 primary; 38 secondary CNS lymphoma). Median age at start of MAITC was 66 years (range 25-90). Only six patients received external beam radiation (EBRT). Median MAITC cycles was 8 (range 2-23). 76% of patients with primary and 66% with secondary CNS lymphoma were alive 1 year after starting MAITC. Of 37 eligible patients, 17 (46%) were alive 3 years after starting MAITC. After a median 19.2 months follow-up, median OS was not reached. No significant difference was noted in OS between primary and secondary CNS lymphoma. KPS &amp;gt; 80 was positively while leptomeningeal disease, secondary CNS lymphoma, and EBRT were negatively associated with OS. Ommaya-related infections occurred in 8 patients (13.5%); only 1 required removal. CONCLUSION Based on our institutional data, MAITC can potentially offer a significant OS advantage with minimal safety concerns. Factors associated with poor survival were identified, which are being addressed in a larger dataset along with baseline CSF biomarkers.

CSF 14-3-3β is associated with progressive cognitive decline in Alzheimer's disease.

Alzheimer's disease is a neurodegenerative disorder characterized pathologically by amyloid-beta plaques, tau tangles and neuronal loss. In clinical practice, the 14-3-3 isoform beta (β) is a biomarker that aids in the diagnosis of sporadic Creutzfeldt-Jakob disease. Recently, a proteomics study found increased CSF 14-3-3β levels in Alzheimer's disease patients, suggesting a potential link between CSF 14-3-3β and Alzheimer's disease. Our present study aimed to further investigate the role of CSF 14-3-3β in Alzheimer's disease by analysing the data of 719 participants with available CSF 14-3-3β measurements from the Alzheimer's Disease Neuroimaging Initiative. Higher CSF 14-3-3β levels were observed in the mild cognitive impairment group compared to the cognitively normal group, with the highest CSF 14-3-3β levels in the Alzheimer's disease dementia group. This study also found significant associations between CSF 14-3-3β levels and CSF biomarkers of p-tau, t-tau, pTau/Aβ42 ratios and GAP-43, as well as other Alzheimer's disease biomarkers such as Aβ-PET. An early increase in CSF 14-3-3β levels was observed prior to Aβ-PET-positive status, and CSF 14-3-3β levels continued to rise after crossing the Aβ-PET positivity threshold before reaching a plateau. The diagnostic accuracy of CSF 14-3-3β (area under the receiver operating characteristic curve = 0.819) was moderate compared to other established Alzheimer's disease biomarkers in distinguishing cognitively normal Aβ pathology-negative individuals from Alzheimer's disease Aβ pathology-positive individuals. Higher baseline CSF 14-3-3β levels were associated with accelerated cognitive decline, reduced hippocampus volumes and declining fluorodeoxyglucose-PET values over a 4-year follow-up period. Patients with mild cognitive impairment and high CSF 14-3-3β levels at baseline had a significantly increased risk [hazard ratio = 2.894 (1.599-5.238), P < 0.001] of progression to Alzheimer's disease dementia during follow-up. These findings indicate that CSF 14-3-3β may be a potential biomarker for Alzheimer's disease and could provide a more comprehensive understanding of the underlying pathological changes of Alzheimer's disease, as well as aid in the diagnosis and monitoring of disease progression.

Acute optic neuritis: What are the clues to the aetiological diagnosis in real life?

Previous cross-sectional studies have reported distinct clinical and radiological features among the different acute optic neuritis (ON) aetiologies. Nevertheless, these reports often included the same number of patients in each group, not taking into account the disparity in frequencies of ON aetiologies in a real-life setting and thus, it remains unclear what are the truly useful features for distinguishing the different ON causes. To determine whether clinical evaluation, ophthalmological assessment including the optical coherence tomography (OCT), CSF analysis, and MRI imaging may help to discriminate the different causes of acute ON in a real-life cohort. In this prospective monocentric study, adult patients with recent acute ON (<1 month) underwent evaluation at baseline and 1 and 12 months, including, high- and low-contrast visual acuity, visual field assessment and OCT measurements, baseline CSF analysis and MRI. Among 108 patients, 71 (65.7%) had multiple sclerosis (MS), 19 (17.6%) had idiopathic ON, 13 (12.0%) and 5 (4.6%) had myelin oligodendrocyte glycoprotein and aquaporin-4 antibodies, at last follow up respectively.At baseline, the distribution of bilateral ON, CSF-restricted oligoclonal bands, optic perineuritis, optic nerve length lesions and positive dissemination in space and dissemination in time criteria on MRI were significantly different between the four groups (p <0.001). No significant difference in visual acuity nor inner retinal layer thickness was found between the different ON aetiologies. In this large prospective study, bilateral visual involvement, CSF and MRI results are the most useful clues in distinguishing the different aetiologies of acute ON, whereas ophthalmological assessments including OCT measurements revealed no significant difference between the aetiologies.

Safety and preliminary efficacy of intrathecal (IT) and intravenous (IV) nivolumab (N) for patients (pts) with leptomeningeal disease (LMD).

9554 Background: Pts with LMD have a dismal prognosis, with median overall survival (OS) &lt; 3 months, no approved therapies and extremely limited clinical trial options. We previously reported initial safety findings from the dose escalation of an open label, single arm, single center phase I/IB trial (NCT03025256) for pts with metastatic melanoma (MM), in which IT/IV N were well tolerated, without any CNS-specific or unexpected toxicity. Here we report an update on safety, maximum tolerated dose (MTD), and dose expansion cohort (including 2 pts with NSCLC) and preliminary efficacy. Methods: Pts aged ≥18 with evidence of LMD by MRI and/or CSF cytology, ECOG PS ≤2 were treated with IT/IV N. Dexamethasone (dexa) ≤4mg/daily and concurrent BRAF/MEK inhibitor(i) therapy (tx) were allowed. For cycle 1, IT N was administered via ommaya reservoir on day (D)1. For subsequent cycles (every 14 days) pts received IT N on D1, followed by IV N 240 mg on D2. IT N doses evaluated were 5, 10, 20, and 50 mg. Blood and CSF were collected at multiple time points for translational research. The primary objectives were to determine safety and/or recommended dose/MTD of IT N given with IV N in pts with LMD and the safety of the MTD in an expansion cohort. OS was a secondary objective. Bayesian mTPI methodology was used to define the MTD. Results: 50 pts were treated: 17 in the dose escalation (2 at 5; 3 at 10; 6 at 20; 6 at 50 mg IT N), 8 in the initial expansion of 20mg, and 25 at the MTD 50 mg IT N. 48 pts had a diagnosis of MM, 2 NSCLC. Median age at LMD was 49 (19-74); 27 pts are male. All pts had radiographic evidence of LMD; 26 pts had positive baseline CSF cytology. 46 pts received prior systemic tx including checkpoint inhibitors (n = 42) and targeted tx (n = 34). 39 pts had prior CNS radiation (RT), including whole brain RT (n = 14). 18 pts used concurrent steroid, with a median dose of 2mg (0.9-4) dexa equivalent and 27 pts used concurrent targeted tx with BRAF/MEKi. The median number of IT N doses was 6 (1- 92). The combination regimen was well tolerated by all evaluable pts (n = 50), with 9 pts (18%) experiencing grade (gr) 3 AEs and no reported gr 4 or 5 toxicities. Rash (58%), nausea (44%), vomiting (34%), and dizziness (22%) were the most common AEs. Thirty pts (60%) experienced AEs after IT N administration, all gr 1/2 and 1 gr 3 (vasogenic edema). At a median follow-up of 4.6 months (mths) (0, 54.8 mths), median OS was 7.0 mths. OS was 66.6% at 3 mths, 53.1% at 6 mths and 34.8% at 12 mths. Conclusions: IT + IV nivo was safe and well-tolerated in MM pts with LMD, with no unexpected toxicities of the 50 mg MTD of IT N. OS rates at 6 and 12 mths are encouraging and support further evaluation of IT immunotherapy for LMD, including in other tumor types. Overall results also demonstrate the feasibility of prospective clinical trials in pts with LMD. Final presentation will also include immunological analysis of longitudinally collected CSF samples collected in the trial. Clinical trial information: NCT03025256 .