Background and Objectives Blood-based biomarkers have emerged as minimally invasive options for evaluating cognitive impairment. Most studies to date have assessed them in research cohorts, limiting their generalization to everyday clinical practice. We evaluated their diagnostic performance and clinical applicability in a prospective, real-world, memory clinic cohort. Methods All patients referred with suspected cognitive impairment between July 2019 and June 2021 were prospectively invited to participate. Five plasma biomarkers (tau phosphorylated at threonine 181 [p-tau181], glial fibrillary acidic protein [GFAP], neurofilament light chain [NfL], total tau [t-tau], and ubiquitin C-terminal hydrolase L1 [UCH-L1]) were determined with single-molecule array. Performance was assessed in comparison to clinical diagnosis (blinded to plasma results) and amyloid status (CSF/PET). A group of cognitively unimpaired (CU) controls was also included. Results Three hundred forty-nine participants (mean age 68, SD 8.3 years) and 36 CU controls (mean age 61.7, SD 8.2 years) were included. In the subcohort with available Alzheimer disease (AD) biomarkers (n = 268), plasma p-tau181 and GFAP had a high diagnostic accuracy to differentiate AD from non-neurodegenerative causes (area under the receiver operating characteristic curve 0.94 and 0.92, respectively), with p-tau181 systematically outperforming GFAP. Plasma p-tau181 levels predicted amyloid status (85% sensitivity and specificity) with accurate individual prediction in approximately 60% of the patients. Plasma NfL differentiated frontotemporal dementia (FTD) syndromes from CU (0.90) and non-neurodegenerative causes (0.93), whereas the discriminative capacity with AD and between all neurodegenerative and non-neurodegenerative causes was less accurate. A combination of p-tau181 and NfL identified FTD with 82% sensitivity and 85% specificity and had a negative predictive value for neurodegenerative diagnosis of 86%, ruling out half of the non-neurodegenerative diagnoses. In the subcohort without AD biomarkers, similar results were obtained. T-tau and UCH-L1 did not offer added diagnostic value. Discussion Plasma p-tau181 predicted amyloid status with high accuracy and could have potentially avoided CSF/amyloid PET testing in approximately 60% of subjects in a memory clinic setting. NfL was useful for identifying FTD from non-neurodegenerative causes but behaved worse than p-tau181 in all other comparisons. Combining p-tau181 and NfL improved diagnostic performance for FTD and non-neurodegenerative diagnoses. However, the 14% false-negative results suggest that further improvement is needed before implementation outside memory clinics. Classification of Evidence This study provides Class I evidence that plasma p-tau181 correlates with the presence or absence of AD and a combination of plasma p-tau181 and NfL correlates moderately well with a diagnosis of FTD.

α-Synuclein seed amplification assays (αSAAs) can improve the diagnosis of synucleinopathies and detect α-synuclein (αSyn) copathology in vivo in clinical practice. We aimed to evaluate the diagnostic performance of αSAA for detecting αSyn in CSF for diagnosing dementia with Lewy bodies (DLB) in a clinical cohort of cognitively impaired individuals. We explored how the coexistence of Alzheimer disease (AD) and αSyn pathology influences biomarker levels and clinical profiles. This study contributes to the understanding of αSAA diagnostic performance for DLB and for detecting αSyn copathology in AD in a real-world memory clinic cohort, using both clinical and biomarker-based classifications. This was a retrospective, single-center, cross-sectional observational cohort study of cognitively impaired individuals who attended a tertiary memory clinic in Spain between 2009 and 2024. Participants had neurodegenerative and non-neurodegenerative cognitive decline. αSAA was performed on CSF samples collected at first evaluation. The diagnostic performance of the assay for DLB and associations between AD/αSyn copathology, clinical features, and fluid biomarkers (phosphorylated-tau217 [p-tau217], glial fibrillary acidic protein, neurofilament light chain [NfL]) were analyzed in AD and DLB participants. Diagnostic performance of the test was assessed using standard contingency tables and interactions between biomarkers and clinical features with age, sex, and APOE-adjusted analysis of covariance. A total of 640 participants were included (mean age 67.8 years, 48% female) with clinical diagnoses of AD (n = 337), DLB (n = 92), frontotemporal lobar degeneration (n = 79), non-neurodegenerative cognitive impairment (n = 100), and cognitively unimpaired controls (n = 32). αSAA exhibited a 95.7% sensitivity (95% CI 91.6%-99.8%), 93.2% specificity (95% CI 90.4%-96.0%), and a 93.6% overall diagnostic accuracy for DLB. Among patients with AD, 9.5% were αSAA positive; these individuals more often had core DLB features at presentation, higher APOE ε4 frequency, and elevated plasma p-tau217. Fifty percent of DLB patients showed AD copathology, associated with lower Mini-Mental State Examination scores, higher APOE ε4 prevalence, and higher CSF and plasma NfL. αSAA+ AD subjects had significantly higher p-tau217 and CSF p-tau181 than DLB AD+ patients. αSAA demonstrated high diagnostic accuracy for DLB, supporting its clinical utility. AD-DLB copathology is associated with distinct cognitive and biomarker profiles, with varying levels of pathology shaping the clinical phenotype (AD- or DLB-predominant). These findings highlight the need for tailored diagnostic and therapeutic approaches.

Ustekinumab, a monoclonal antibody against interleukin (IL)-12 and IL-23 approved for the treatment of Crohn’s disease, has shown to be an effective therapy with a favourable safety profile. Clinical trials and real-world studies have reported very few neurological adverse events, including posterior reversible encephalopathy syndrome, idiopathic intracranial hypertension and headache. We describe the case of a 48-year-old man with Crohn’s disease who initiated treatment with ustekinumab on top of ongoing treatment with methotrexate 25 mg/week who presented with an acute-onset encephalopathy that rapidly evolved to severe tetraparesis and akinetic mutism, associated with extensive leukoencephalopathy and restricted diffusion on brain magnetic resonance imaging (MRI), 1 month after the second dose of ustekinumab. Comprehensive in-patient diagnostic testing ruled out vascular, demyelinating, metabolic, tumoral and infectious etiologies. Brain biopsy showed patchy infiltrates of foamy histiocytes with perivascular distribution, associated with edema, diffuse astrocytic gliosis and focal perivascular axonal destruction without demyelination, and ustekinumab-induced neurotoxicity was suspected. After drug discontinuation, the patient presented a complete clinical recovery despite the persistence of leukoencephalopathy. In conclusion, in an era in which biological therapies are continually evolving and expanding, knowledge about the potential neurotoxicity of these new therapies and their management becomes crucial. Although ustekinumab-induced encephalopathy is uncommon, the recognition of this potentially serious side effect is important because prompt withdrawal is associated with a favourable outcome. Whether methotrexate played an additional contributing role is currently unknown, but it is a factor that should be considered.