Berthold Pemp

Background: The relationship between intrathecal kappa free light chain (κ‐FLC) synthesis and retinal layer atrophy in multiple sclerosis (MS) is unknown. Objective: To investigate whether the κ‐FLC index is associated with peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell plus inner plexiform layer (GCIPL) thickness. Methods: Patients with newly diagnosed clinically isolated syndrome or relapsing MS and available cerebrospinal fluid (CSF) analysis and optical coherence tomography (OCT) were included. Clinical and magnetic resonance imaging (MRI) data were also assessed. κ‐FLC concentrations were measured by nephelometry, and the κ‐FLC index was calculated as (CSF κ‐FLC/serum κ‐FLC)/albumin quotient. Results: A total of 100 patients at a median age of 33 (25th–75th percentile: 25–39) years and a female predominance (58%) were included. In multivariable linear regression analysis adjusted for age, sex, disease duration, number of T2‐hyperintense and number of contrast‐enhancing MRI lesions, the κ‐FLC index was associated with pRNFL (log‐transformed κ‐FLC index: β : −2.51; 95% confidence interval [CI]: −4.01, −1.01; p = 0.001) and GCIPL thinning (log‐transformed κ‐FLC index: β : −1.24, 95% CI: −2.32, −0.17; p = 0.024). Conclusions: Intrathecal plasma cell activity, as measured by the κ‐FLC index, is associated with neuroaxonal damage, as reflected by pRNFL and GCIPL atrophy.

Objectives: The pathophysiology of idiopathic intracranial hypertension (IIH) is poorly understood and disease‐specific biomarkers are lacking. We aimed to shed light on IIH pathophysiology and identify disease‐specific biomarkers. Methods: This prospective cross‐sectional cohort study included patients with new‐onset IIH and age‐, body mass index‐, and sex‐matched healthy controls from 2 tertiary Danish Headache Centers (discovery cohort). Liquid chromatography coupled to tandem mass spectrometry analysis was used to measure reproducible proteomic profiles for paired serum and cerebrospinal fluid (CSF) samples. Results were validated using 3 validation cohorts comprising patients with IIH (pwIIH), cerebral sinus venous thrombosis (pwCSVT), and normal pressure hydrocephalus (pwNPH). Results: We included 53 pwIIH and 35 controls. PwIIH presented with papilledema and increased median lumbar puncture opening pressure (interquartile range [IQR]) (38.0 [33–46] vs 19.0 [17.0–23.0] cmH ₂ O; p < 0.001) compared to controls. Machine learning analysis identified 20 IIH‐predicting proteins for serum and CSF segregating pwIIH, but neither pwCSVT nor pwNPH, from controls with areas under the curve (AUC) of 0.84 and 0.92 (pwIIH, discovery cohort), 0.99 and 0.90 (pwIIH, validation cohort 1), 0.63 (plasma; pwCSVT), and 0.67 (CSF; pwNPH), respectively. Serum carbonic anhydrases (CA) 1 and 2 were upregulated and among the most IIH‐predicting proteins as were amyloid precursor protein (APP), S100P, and S100A12. Interpretation: We identified a panel of independently validated IIH‐specific candidate biomarkers. The serum candidate biomarkers pointed toward CA2 driven CSF hypersecretion in IIH providing a possible explanation for the therapeutic efficacy of CA inhibitors. The regulation of markers associated with neuronal impairment (APP, S100P/S100A12) confirmed the non‐benign character of IIH. ANN NEUROL 2026

Objective: We aimed to assess whether modified OCT acquisition parameters improve GCIPL measurement reliability. Methods: Participants with multiple sclerosis (PwMS) and age- and sex-matched healthy controls (HC) underwent OCT (Spectralis OCT, Heidelberg Engineering, Heidelberg, Germany) at baseline and after two and four weeks. At each visit, five macular scan protocols were acquired: standard (49 lines, high-speed [HS], automated real-time tracking [ART]: 9), high-ART (49 lines, HS, ART: 50), high-lines (97 lines, HS, ART: 9), high-resolution (49 lines, high-resolution [HR], ART: 9), and maximum (97 lines, HR, ART: 50). Reliability was assessed using intraclass correlation coefficients (ICC). Absolute test–retest reproducibility was quantified using the mean absolute difference (MAD). Results: Thirty-eight eyes from nine PwMS (mean age 34.1 ± 8.0 years, 44.4% female) and ten HC (31.7 ± 11.1 years, 50.0% female) were included. At baseline, mean GCIPL thickness ranged from 70.8 µm to 71.5 µm across protocols, demonstrating excellent inter-protocol agreement (ICC 0.99; 95% confidence interval [CI]: 0.98–0.99; p < 0.001) and only marginally higher values with increased ART. Test–retest reliability was excellent for all protocols, demonstrating marginally lower absolute measurement variability of high-ART and high-lines protocols (MAD 0.26–0.27; 95% CI: 0.21–0.32), while temporal agreement remained excellent and comparable across acquisition settings. Mean acquisition time ranged from 10.6 ± 1.6 s for the standard protocol to 231.9 ± 36.4 s for the maximum protocol. Conclusions: All OCT acquisition protocols demonstrated excellent inter-protocol and test–retest reliability for GCIPL measurements. The high-lines protocol provides the most favourable balance between measurement reliability and acquisition time, supporting its potential utility for longitudinal GCIPL monitoring.

Objective. To assess whether modified OCT acquisition parameters improve GCIPL measurement reliability. Methods. Participants with multiple sclerosis (pwMS) and age- and sex-matched healthy controls (HC) underwent OCT (Spectralis OCT, Heidelberg Engineering, Heidelberg, Germany) at baseline and after two and four weeks. At each visit, five macular scan protocols were acquired: standard (49 lines, high-speed [HS], automated real-time tracking [ART]: 9), high-ART (49 lines, HS, ART: 50), high-lines (97 lines, HS, ART: 9), high-resolution (49 lines, high-resolution [HR], ART: 9), and maximum (97 lines, HR, ART: 50). Reliability was assessed using intraclass correlation coefficients (ICC). Absolute test-retest reproducibility was quantified using the mean absolute difference (MAD). Results. Thirty-eight eyes from nine pwMS (mean age 34.1±8.0 years, 44.4% female) and ten HC (31.7±11.1 years, 50.0% female) were included. At baseline, mean GCIPL thickness ranged from 70.8µm to 71.5µm across protocols, demonstrating excellent inter-protocol agreement (ICC 0.99; 95% confidence interval [CI]: 0.98-0.99; p< 0.001) and only marginally higher values with increased ART. Test-retest reliability was excellent for all protocols, demonstrating marginally lower absolute measurement variability of high-ART and high-lines protocols (MAD 0.26-0.27; 95% CI: 0.21-0.32), while temporal agreement remained excellent and comparable across acquisition settings. Mean acquisition time ranged from 10.6±1.6s for the standard protocol to 231.9±36.4s for the maximum protocol. Conclusions. All OCT acquisition protocols demonstrated excellent inter-protocol and test-retest reliability for GCIPL measurements. The high-lines protocol provides the most favourable balance between measurement reliability and acquisition time, supporting its potential utility for longitudinal GCIPL monitoring.

Inner retinal layer thinning in autosomal dominant optic atrophy (ADOA) can affect visual acuity (VA), but impact on perimetric parameters and disease-related changes with increasing age are undefined. One hundred eight patients with ADOA harboring a disease-causing variant in OPA1 were analyzed retrospectively, including best-corrected VA, mean deviation (MD) from 30-2 threshold perimetry, MD in the papillomacular bundle (PMB) subfield, and retinal layer thickness in spectral-domain optical coherence tomography (OCT). Twenty-three of 57 detected variants in OPA1 are newly reported. In multivariable mixed-effect models, peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell layer (mGCL) thicknesses impacted visual function, with an average deterioration of 0.1 logMAR per 3.2 µm mGCL reduction (P < 0.001), PMB-MD loss of 0.75 dB/µm mGCL (P = 0.002), and MD loss of 0.11 dB/µm pRNFL (P = 0.048). Age impacted mGCL thickness (-0.06 µm/year; P = 0.023). In available long-term follow-ups mGCL lost 0.26 ± 0.10 µm/year. Missense variants caused worse VA (0.83 vs. 0.49 logMAR, P = 0.016), MD (-11.48 vs. -3.04 decibel [dB], P = 0.005), and PMB-MD (-16.25 vs. -4.17 dB, P = 0.001) than haploinsufficiency variants, and lower mGCL (20.12 vs. 21.97 µm, P = 0.044) and pRNFL thickness (52.41 vs. 66.41 µm, P < 0.001). VA and central scotoma severity in OPA1-related ADOA are significantly associated with inner retinal layer thickness, which is impacted by patient age. The mGCL thickness and sensitivity in the PMB subfield were the most indicative clinical parameters for disease-related changes, with worse outcomes in heterozygotes with missense variants in OPA1.

Progression independent of relapse activity (PIRA) is the main driver of disability accumulation in relapsing multiple sclerosis (RMS). Retinal layer atrophy measured by optical coherence tomography (OCT) reflects neuroaxonal damage and is associated with PIRA. However, it remains unclear whether this association is driven by subclinical inflammatory activity or reflects true progression independent of acute inflammation. Here, we aimed to investigate the relationship between retinal layer atrophy and progression independent of relapse and MRI activity (PIRMA) to clarify the impact of subclinical inflammatory activity. From an ongoing prospective observational study, patients with RMS meeting the following criteria were included: an OCT scan conducted 3-6 months after disease-modifying treatment (DMT) initiation (rebaseline) and at least one follow-up OCT after ≥12 months. Disability accrual was defined as a composite measure comprising worsening in either Expanded Disability Status, Timed 25-Foot Walk Test, 9-Hole Peg Test, or Symbol Digit Modalities Test using a roving baseline with a 6-month confirmation interval. PIRA was defined as disability accrual without relapse between roving baseline and confirmation. PIRMA was defined as PIRA that remained radiologically silent. We evaluated associations between PIRMA and thinning of the peripapillary retinal nerve fiber layer (pRNFL) and the macular ganglion cell plus inner plexiform layer (GCIPL) using multivariable mixed-effects linear regression models adjusted for relevant covariables (age, sex, disease duration, GCIPL/pRNFL at rebaseline, and moderate vs high-efficacy DMT). A total of 210 patients with RMS (mean age 30.5 years, SD 7.9; 74.1% female) were analyzed over a median observation period of 2.3 years (range 1-5.9 years). PIRMA was observed in 28 (13.3% overall, 41.8% of all disability accruals, 54.1% of PIRA) patients, while PIRA was encountered in 50 (23.8% overall, 77.2% of all disability accruals). Multivariable models revealed that PIRMA (vs no PIRMA) was associated with significantly more pronounced thinning of both GCIPL (0.72% per year, 95% CI 0.50-0.82, p < 0.001) and pRNFL (1.05% per year, 95% CI 0.89-1.18, p < 0.001). Our findings indicate that retinal atrophy is significantly linked with PIRMA, reinforcing its potential as a biomarker of MS-related neuroaxonal degeneration that occurs independently of acute focal inflammation.

Background: Serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (GFAP) are emerging biomarkers of axonal damage and astrocytic activation. The value of sNfL and GFAP in predicting retinal layer thinning remains underexplored. Objectives: To evaluate the association between sNfL and GFAP levels and retinal layer thinning. Methods: This prospective observational study included people with relapsing MS (pwMS) newly initiated on a disease-modifying therapy (DMT). Optical coherence tomography (OCT) scans were conducted 3–6 months after DMT initiation and at 12-month intervals measuring peripapillary retinal nerve fibre layer (pRNFL) and ganglion cell-inner plexiform layer (GCIPL) thickness. sNfL and GFAP levels were measured at baseline and after 6 months (M6) using single-molecule array (Simoa ^® ) technology. Results: A total of 116 pwMS (mean age 34.5 years [SD 8.6]), 73.3% female) were included. GFAP z-scores at M6 showed the strongest association with annualized loss of pRNFL (aLpRNFL: b = −0.24; 95% confidence interval [CI] −0.27, −0.21, p < 0.001) and GCIPL (aLGCIPL: b = −0.15; 95% CI: −0.18, −0.12, p < 0.001). Moreover, pwMS with low sNfL but high GFAP levels at M6 showed the most pronounced retinal layer thinning (aLpRNFL: −0.8%/year [1.1], aLGCIPL: −0.8%/year [0.9]; both p < 0.001). Conclusions: High GFAP levels – more than sNfL levels – are associated with retinal layer thinning in relapsing MS.

Objective: To investigate whether the rs10191329 risk allele in the DYSF–ZNF638 locus, which is implicated in central nervous system resilience rather than immune‐mediated pathology, is associated with retinal layer thinning, a biomarker of neuroaxonal damage in relapsing multiple sclerosis (RMS). Methods: From a prospective observational study, we included RMS patients with ≥ 2 optical coherence tomography (OCT) scans, excluding eyes with optic neuritis during the observation period. DNA samples were genotyped using the Illumina Infinium Global Screening Array‐24 and variants imputed using the Haplotype Reference Consortium panel and Minimac4. Multivariable linear regression models were used to assess the association between rs10191329 risk allele number (rs10191329*A) and annualized rates of peripapillary retinal nerve fiber layer (aLpRNFL) and macular ganglion‐cell‐and‐inner‐plexiform‐layer (aLGCIPL) atrophy, adjusting for age, sex, MS‐specific variables, and 10 ancestry components. Results: We included 183 RMS patients (mean age 35.9 years [SD 9.6], 74.9% female, median EDSS 2.0 [range 0–6.5], median observation 25 months [12–73], median OCT scans 3 [2–5]). Multivariable analyses revealed that each rs10191329*A allele was associated with a 0.10%/year increase in aLpRNFL (95% confidence interval [CI] 0.05–0.19, p < 0.001) and a 0.11%/year increase in aLGCIPL (95% CI 0.07–0.19, p < 0.001). The rs10191329 variant explained 8.9% of GCIPL atrophy and 8.2% of pRNFL atrophy variance. Interpretation: Carriers of the rs10191329 risk allele show accelerated retinal atrophy, suggesting heightened neuroaxonal vulnerability in MS. While clinical implications are currently unclear, genetic stratification may be reasonable in clinical trials targeting neuroprotection.