Cerebrospinal fluid profiles with increasing number of cerebral microbleeds in a continuum of cognitive impairment.

Cerebral microbleeds (CMBs) are hypothesised to have an important yet unknown role in the dementia disease pathology. In this study we analysed increasing number of CMBs and their independent associations with routine cerebrospinal fluid (CSF) biomarkers in a continuum of cognitive impairment. A total of 1039 patients undergoing dementia investigation were analysed and underwent lumbar puncture, and an MRI scan. CSF samples were analysed for amyloid β (Aβ) 42, total tau (T-tau), tau phosphorylated at threonine 18 (P-tau) and CSF/serum albumin ratios. Increasing number of CMBs were independently associated with low Aβ42 levels, in the whole cohort, Alzheimer's disease and mild cognitive impairment (p < 0.05). CSF/serum albumin ratios were high with multiple CMBs (p < 0.001), reflecting accompanying blood-brain barrier dysfunction. T-tau and P-tau levels were lower in Alzheimer's patients with multiple CMBs when compared to zero CMBs, but did not change in the rest of the cohort. White matter hyperintensities were associated with low Aβ42 in the whole cohort and Alzheimer's disease (p < 0.05). Aβ42 is the routine CSF-biomarker mainly associated with CMBs in cognitive impairment, and there is an accumulative effect with increasing number of CMBs.

Shams S ，Granberg T ，Martola J ，Li X ，Shams M ，Fereshtehnejad SM ，Cavallin L ，Aspelin P ，Kristoffersen-Wiberg M ，Wahlund LO ... -  《-》

Cerebral microbleeds topography and cerebrospinal fluid biomarkers in cognitive impairment.

Shams S ，Granberg T ，Martola J ，Charidimou A ，Li X ，Shams M ，Fereshtehnejad SM ，Cavallin L ，Aspelin P ，Wiberg-Kristoffersen M ，Wahlund LO ... -  《-》

Data-driven CSF biomarker profiling: imaging and clinical outcomes in a cohort at risk of Alzheimer's disease.

Cerebrospinal fluid (CSF) biomarkers of synaptic dysfunction, neuroinflammation, and glial response, complementing Alzheimer's disease (AD) core biomarkers, have improved the pathophysiological characterization of the disease. Here, we tested the hypothesis that the co-expression of multiple CSF biomarkers will help the identification of AD-like phenotypes when biomarker positivity thresholds are not met yet. Two hundred and seventy cognitively unimpaired adults with family history (FH) of sporadic AD (mean age = 60.6 ± 4.85 years, 64.8% women) underwent lumbar puncture, magnetic resonance imaging (n = 266) and positron emission tomography imaging (n = 239) protocols, and clinical evaluations. CSF Aβ42, Aβ40, p-tau181, p-tau217, p-tau231, NfL, neurogranin, sTREM2, YKL40, GFAP, S100, α-Synuclein, SYT1, and SNAP25 were measured. Participants were clustered based on CSF biomarker co-expression with an agglomerative algorithm. The predictive value of the classification against brain and cognitive outcomes was evaluated. Three clusters (C) were identified. Higher Aβ burden and CSF p-tau was the hallmark of C1. The other two clusters showed lower Aβ burden but higher expression of glial (C2) or synaptic markers (C3). Participants in C1 showed an AD-like clinical phenotype, comprising participants with the overall highest percentage of two parent FH and APOE-ε4 carriers, in addition to comprising more females compared to C2. C3 displayed better vascular health compared to C1. C2 were older and comprised a lower percentage of females compared to C3. C1 showed an AD-like gray matter reduction in medial temporal (notably hippocampus) and frontal regions that were not observed in Aβ42/40 + compared with Aβ42/40 - . Furthermore, Aβ42/40 - participants in C1 showed GM reduction in inferior temporal areas compared with Aβ42/40 + participants overall. C1 membership also predicted cognitive decline in executive function, but not memory, beyond Aβ + status, overall suggesting a better prognosis in Aβ42/40 + participants without C1 membership. Additionally, C1 displayed a higher rate of conversion to Aβ + (25%) over time. Our results suggest that examining multiple CSF biomarkers reflecting diverse pathological pathways may complement and/or outperform AD core biomarkers and thresholding approaches to identify individuals showing a clinical and cognitive AD-like phenotype, including higher conversion to Aβ + , GM reductions and cognitive decline. The clinical utility of this approach warrants further investigation and replication in other cohorts.

Argiris G ，Akinci M ，Peña-Gómez C ，Palpatzis E ，Garcia-Prat M ，Shekari M ，Blennow K ，Zetterberg H ，Kollmorgen G ，Quijano-Rubio C ，Ashton NJ ，Karikari TK ，Brinkmalm-Westman A ，Lantero-Rodriguez J ，Fauria K ，Sánchez-Benavides G ，Grau-Rivera O ，Suárez-Calvet M ，Arenaza-Urquijo EM ，Study FTA ... -  《Alzheimers Research & Therapy》

Brain derived β-interferon is a potential player in Alzheimer's disease pathogenesis and cognitive impairment.

Recent research has postulated that the activation of cGAS-STING-interferon signalling pathways could be implicated in the pathogenesis of Alzheimer's disease (AD). However, the precise types of interferons and related cytokines, both from the brain and periphery, responsible for cognitive impairment in patients with AD remain unclear. A total of 131 participants (78 [59.5%] female and 53 [40.5%] male; mean [SD] age, 61.5 [7.6] years) with normal cognition and cognitive impairment from the China Aging and Neurodegenerative Initiative cohort were included. CSF and serum IFNα-2a, IFN-β, IFN-γ, TNF-α, IL-6, IL-10, MCP-1and CXCL-10 were tested. The correlation between these interferons and related cytokines with AD core biomarkers in the CSF and plasma, cognition performance, and brain MRI measures were analysed. We found that only CSF IFN-β levels were significantly elevated in Alzheimer's disease compared to normal cognition. Furthermore, CSF IFN-β levels were significantly associated with AD core biomarkers (CSF P-tau and Aβ42/Aβ40 ratio) and cognitive performance (MMSE and CDR score). Additionally, the CSF IFN-β levels were significantly correlated with the typical pattern of brain atrophy in AD (such as hippocampus, amygdala, and precuneus). In contrast, CSF IL-6 levels were significantly elevated in non-AD cognitively impaired patients compared to other groups. Moreover, CSF IL-6 levels were significantly associated with cognitive performance in non-AD individuals and correlated with the vascular cognitive impairment-related MRI markers (such as white matter hyperintensity). Our findings demonstrate that distinct inflammatory molecules are associated with different cognitive disorders. Notably, CSF IFN-β levels are significantly linked to the pathology and cognitive performance of AD, identifying this interferon as a potential target for AD therapy.

Wang Q ，Yuan S ，Wang C ，Huang D ，Zhang M ，Zhan Y ，Gao F ，Shi J ，Levey AI ，Shen Y ... -  《Alzheimers Research & Therapy》

Association of CSF α-synuclein seed amplification assay positivity with disease progression and cognitive decline: A longitudinal Alzheimer's Disease Neuroimaging Initiative study.

Cerebrospinal fluid (CSF) α-synuclein (α-syn) seed amplification assay (SAA) is a sensitive and specific tool for detecting Lewy body co-pathology in Alzheimer's disease. A total of 1637 cross-sectional and 407 longitudinal CSF samples from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were tested with SAA. We examined longitudinal dynamics of amyloid beta (Aβ), α-syn seeds, and phosphorylated tau181 (p-tau181), along with global and domain-specific cognition in stable SAA+, stable SAA-, and those who converted to SAA+ from SAA-. SAA+ individuals had faster cognitive decline than SAA-, notably in mild cognitive impairment, and presented with earlier symptom onset. SAA+ conversion was associated with CSF Aβ42 positivity but did not impact the progression of either CSF Aβ42 or CSF p-tau181 status. CSF Aβ42, p-tau181, and α-syn SAA were all strong predictors of clinical progression, particularly CSF Aβ42. In vitro, CSF α-syn SAA kinetic parameters were associated with participant demographics, clinical profiles, and cognitive decline. These results highlight the interplay between amyloid and α-syn and their association with disease progression. Seed amplification assay (SAA) positivity was associated with greater cognitive decline and earlier symptom onset. Thirty-four Alzheimer's Disease Neuroimaging Initiative (ADNI) individuals progressed from SAA- to SAA+, that is, ≈ 5% conversion. SAA conversion was associated with amyloid beta (Aβ) pathology and greater cognitive decline. SAA status did not impact the progression of either CSF Aβ42 or phosphorylated tau181 biomarkers. Change in clinical diagnosis was associated with both Alzheimer's disease biomarkers and SAA. SAA kinetic parameters were associated with clinical features and progression.

Tosun D ，Hausle Z ，Thropp P ，Concha-Marambio L ，Lamoureux J ，Lebovitz R ，Shaw LM ，Singleton AB ，Weiner MW ，Alzheimer's Disease Neuroimaging Initiative ，Blauwendraat C ... -  《-》