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Objective: This study examined the effect of cognitive status, education, and sex on the association between subjective cognitive decline (SCD) and Alzheimer's disease (AD) biomarkers in non-demented older adults., Methods: Vanderbilt Memory and Aging Project participants (n = 129), dementia or stroke free, completed fasting lumbar puncture, SCD assessment, and cognitive assessment. Cerebrospinal fluid (CSF) biomarkers for AD were analyzed. Linear regression models related SCD to CSF AD biomarkers and follow-up models assessed interactions of SCD × cognitive status, sex, reading level, and education on AD biomarkers., Results: In main effect models, higher SCD was associated with more amyloidosis (p-values <0.004). SCD was not associated with tau, p-tau, or neurofilament light (NFL) levels (p-values >0.38). SCD score interacted with cognitive status (p < 0.02), sex (p = 0.03), and education (p-values <0.005) on amyloidosis. In stratified models, higher SCD was associated with more amyloid in cognitively unimpaired (p-values <0.003), men (p = 0.0003), and higher education. No SCD score × reading-level interaction was found (p-values >0.51) though SCD related to amyloid markers in the higher reading-level group (p-values <0.004)., Interpretation: Higher SCD was associated with greater cerebral amyloid accumulation, one of the earliest pathological AD changes. SCD appears most useful in detecting early AD-related brain changes prior to objective cognitive impairment, in men, and those with higher quantity and quality of education and highlight the importance of considering these factors., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objective: More than half of neurodegenerative disease patients have multiple pathologies at autopsy; however, most receive one diagnosis during life. We used the α-synuclein seed amplification assay (αSyn-SAA) and CSF biomarkers for amyloidosis and Alzheimer's disease (AD) neuropathological change (ADNC) to determine the frequency of co-pathologies in participants clinically diagnosed with Lewy body (LB) disease or AD., Methods: Using receiver operating characteristic analyses on retrospective CSF samples from 150 participants determined αSyn-SAA accuracy, sensitivity, and specificity for identifying clinically defined LB disease and predicting future change in clinical diagnosis. CSF biomarkers helped determine the frequency of concomitant Lewy body pathology, ADNC, and/or amyloidosis in participants with LB disease and AD, across clinical spectra., Results: Following a decade-long follow-up, the clinically or autopsy-defined diagnosis changed for nine participants. αSyn-SAA demonstrated improved accuracy (91.3%), sensitivity (89.3%), and specificity (93.3%) for identifying LB disease compared to all non-LB disease, highlighting the limitations of clinical diagnosis alone. When examining biomarkers of co-pathology, amyloidosis was present in 18%, 48%, and 71% (χ 2 (2) = 13.56, p = 0.001) and AD biomarkers were present in 0%, 8.7%, and 42.9% (χ 2 (2) = 18.44, p < 0.001) of LB disease participants with different stages of cognitive impairment respectively. Co-occurring biomarkers for αSyn-SAA and amyloidosis were present in 12% and 14% of AD compared to 43% and 57% LB disease participants with different stages of cognitive impairment (χ 2 (3) = 13.87, p = 0.003)., Interpretation: Our study shows that using a combination of αSyn-SAA and AD biomarkers can identify people with αSyn, ADNC, and co-pathology better and earlier than traditional clinical diagnostic criteria alone., (© 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Postoperative neurocognitive decline is a frequent complication in adult patients undergoing major surgery with increased risk for morbidity and mortality. The mechanisms behind cognitive decline after anaesthesia and surgery are not known. We studied the association between CSF and blood biomarkers of neuronal injury or brain amyloidosis and long-term changes in neurocognitive function., Methods: In patients undergoing major orthopaedic surgery (knee or hip replacement), blood and CSF samples were obtained before surgery and then at 4, 8, 24, 32, and 48 h after skin incision through an indwelling spinal catheter. CSF and blood concentrations of total tau (T-tau), neurofilament light, neurone-specific enolase and amyloid β (Aβ1-42) were measured. Neurocognitive function was assessed using the International Study of Postoperative Cognitive Dysfunction (ISPOCD) test battery 1-2 weeks before surgery, at discharge from the hospital (2-5 days after surgery), and at 3 months after surgery., Results: CSF and blood concentrations of T-tau, neurone-specific enolase, and Aβ1-42 increased after surgery. A similar increase in serum neurofilament light was seen with no overall changes in CSF concentrations. There were no differences between patients having a poor or good late postoperative neurocognitive outcome with respect to these biomarkers of neuronal injury and Aβ1-42., Conclusions: The findings of the present explorative study showed that major orthopaedic surgery causes a release of CSF markers of neural injury and brain amyloidosis, suggesting neuronal damage or stress. We were unable to detect an association between the magnitude of biomarker changes and long-term postoperative neurocognitive dysfunction., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Alzheimer's disease (AD) pathology precedes symptoms and its detection can identify at-risk individuals who may benefit from early treatment. Since the retinal nerve fiber layer (RNFL) is depleted in established AD, we tested whether its thickness can predict whether cognitively healthy (CH) individuals have a normal or pathological cerebrospinal fluid (CSF) Aß42 (A) and tau (T) ratio., Methods: As part of an ongoing longitudinal study, we enrolled CH individuals, excluding those with cognitive impairment and significant ocular pathology. We classified the CH group into two sub-groups, normal (CH-NAT, n = 16) or pathological (CH-PAT, n = 27), using a logistic regression model from the CSF AT ratio that identified >85% of patients with a clinically probable AD diagnosis. Spectral-domain optical coherence tomography (OCT) was acquired for RNFL, ganglion cell-inner plexiform layer (GC-IPL), and macular thickness. Group differences were tested using mixed model repeated measures and a classification model derived using multiple logistic regression., Results: Mean age (± standard deviation) in the CH-PAT group (n = 27; 75.2 ± 8.4 years) was similar (p = 0.50) to the CH-NAT group (n = 16; 74.1 ± 7.9 years). Mean RNFL (standard error) was thinner in the CH-PAT group by 9.8 (2.7) μm; p < 0.001. RNFL thickness classified CH-NAT vs. CH-PAT with 87% sensitivity and 56.3% specificity., Conclusions: Our retinal data predict which individuals have CSF biomarkers of AD pathology before cognitive deficits are detectable with 87% sensitivity. Such results from easy-to-acquire, objective and non-invasive measurements of the RNFL merit further study of OCT technology to monitor or screen for early AD pathology., Competing Interests: The authors have declared that no competing interests exist.

Objective: To investigate the relationship between cerebrospinal fluid (CSF) β-amyloid peptide (Aβ42) and CSF Tau in a large population of patients referred to memory clinics for investigation of cognitive dysfunction., Methods: We analyzed Alzheimer's disease (AD) biomarkers in CSF taken from 3565 patients referred to 18 French memory clinics. Patients were classified into four profiles according to levels of CSF biomarkers (A: amyloidosis, N: neurodegeneration). The association between CSF Tau and CSF Aβ42 were analyzed using general linear regression models, in the overall population and stratified by biomarkers profiles. We compared linear and quadratic models using Akaike information criterion. We also assessed change in biomarker profiles in a subset of patients who had 2 assessments of biomarkers., Results: CSF Tau was negatively associated with CSF Aβ42 in the overall population, following a non-linear quadratic model. However, the nature of this association was different in the 4 profiles: positive association in A-N- profile, negative association in A-N+ and A+N+ profiles, lack of association in A+N- patients. When considering patients with longitudinal data on profiles, 36% of those initially classified as A-N+ evolved to an A+N+ profile., Conclusions: The nature of the association between CSF Aβ42 and CFS Tau depends on the A/N profiles of patients. These results suggest an increase in CSF Aβ42 early in the disease before its decline while tau pathology progresses, this pattern is particularly observed in non-APOE4 subjects. This phenomenon may explain why some patients with neurodegeneration only markers convert to an AD profile (A+N+) over time., Competing Interests: The authors have declared that no competing interests exist.

Background: Cholinergic dysfunction is a key abnormality in Alzheimer disease (AD) that can be detected in vivo with transcranial magnetic stimulation (TMS) protocols. Although TMS has clearly demonstrated analytical validity, its clinical utility is still debated. In the present study, we evaluated the incremental diagnostic value, expressed in terms of diagnostic confidence of Alzheimer disease (DCAD; range 0-100), of TMS measures in addition to the routine clinical diagnostic assessment in patients evaluated for cognitive impairment as compared with validated biomarkers of amyloidosis., Methods: One hundred twenty patients with dementia were included and scored in terms of DCAD in a three-step assessment based on (1) demographic, clinical, and neuropsychological evaluations (clinical work-up); (2) clinical work-up plus amyloid markers (cerebrospinal fluid or amyloid positron emission tomographic imaging); and (3) clinical work-up plus TMS intracortical connectivity measures. Two blinded neurologists were asked to review the diagnosis and diagnostic confidence at each step., Results: TMS measures increased the discrimination of DCAD in two clusters (AD-like vs FTD-like) when added to the clinical and neuropsychological evaluations with levels comparable to established biomarkers of brain amyloidosis (cluster distance of 55.1 for clinical work-up alone, 76.0 for clinical work-up plus amyloid markers, 80.0 for clinical work-up plus TMS). Classification accuracy for the "gold standard" diagnosis (dichotomous - AD vs FTD - variable) evaluated in the three-step assessment, expressed as AUC, increased from 0.82 (clinical work-up alone) to 0.98 (clinical work-up plus TMS) and to 0.99 (clinical work-up plus amyloidosis markers)., Conclusions: TMS in addition to routine assessment in patients with dementia has a significant effect on diagnosis and diagnostic confidence that is comparable to well-established amyloidosis biomarkers.

The risk of Alzheimer's disease (AD) is highly dependent on apolipoprotein-E (apoE) genotype. The reasons for apoE isoform-selective risk are uncertain; however, both the amounts and structure of human apoE isoforms have been hypothesized to lead to amyloidosis increasing the risk for AD. To address the hypothesis that amounts of apoE isoforms are different in the human CNS, we developed a novel isoform-specific method to accurately quantify apoE isoforms in clinically relevant samples. The method utilizes an antibody-free enrichment step and isotope-labeled physiologically relevant lipoprotein particle standards produced by immortalized astrocytes. We applied this method to a cohort of well characterized clinical samples and observed the following findings. The apoE isoform amounts are not different in cerebrospinal fluid (CSF) from young normal controls, suggesting that the amount of apoE isoforms is not the reason for risk of amyloidosis prior to the onset of advanced age. We did, however, observe an age-related increase in both apoE isoforms. In contrast to normal aging, the presence of amyloid increased apoE3, whereas apoE4 was unchanged or decreased. Importantly, for heterozygotes, the apoE4/apoE3 isoform ratio was increased in the CNS, although the reverse was true in the periphery. Finally, CSF apoE levels, but not plasma apoE levels, correlated with CSF β-amyloid levels. Collectively, these findings support the hypothesis that CNS and peripheral apoE are separate pools and differentially regulated. Furthermore, these results suggest that apoE mechanisms for the risk of amyloidosis and AD are related to an interaction between apoE, aging, and the amount of amyloid burden., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

We aimed to identify cerebrospinal fluid (CSF) biomarkers associated with neurodegeneration in individuals with and without CSF evidence of Alzheimer pathology. We investigated 287 Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects (age=74.9±6.9; 22/48/30% with Alzheimer's disease/mild cognitive impairment/controls) with CSF multiplex analyte data and serial volumetric MRI. We calculated brain and hippocampal atrophy rates, ventricular expansion and Mini Mental State Examination decline. We used false discovery rate corrected regression analyses to assess associations between CSF variables and atrophy rates in individuals with and without amyloid pathology, adjusting in stages for tau, baseline volume, p-tau, age, sex, ApoE4 status and diagnosis. Analytes showing statistically significant independent relationships were entered into reverse stepwise analyses. Adjusting for tau, baseline volume, p-tau, age, sex and ApoE4, 4/83 analytes were significantly independently associated with brain atrophy rate, 1/83 with ventricular expansion and 2/83 with hippocampal atrophy. The strongest CSF predictor for the three atrophy measures was low trefoil factor 3 (TFF3). High cystatin C (CysC) was associated with higher whole brain atrophy and hippocampal atrophy rates. Lower levels of vascular endothelial growth factor and chromogranin A (CrA) were associated with higher whole brain atrophy. In exploratory reverse stepwise analyses, lower TFF3 was associated with higher rates of whole brain, hippocampal atrophy and ventricular expansion. Lower levels of CrA were associated with higher whole brain atrophy rate. The relationship between low TFF3 and increased hippocampal atrophy rate remained after adjustment for diagnosis. We identified a series of CSF markers that are independently associated with rate of neurodegeneration in amyloid-positive individuals. TFF3, a substrate for NOTCH processing may be an important biomarker of neurodegeneration across the Alzheimer spectrum.

An abnormally low level of cystatin C in the cerebrospinal fluid is a diagnostic marker for the hereditary form of brain hemorrhage associated with amyloidosis that was first identified in Iceland. We developed an assay for cystatin C to use in the diagnosis of patients with cerebral amyloid angiopathy and brain hemorrhage. This test consists of a sandwich enzyme-linked immunosorbent assay using monoclonal mouse anticystatin C and polyclonal rabbit anticystatin C antibodies. The cystatin C level was assayed in cerebrospinal fluid samples from 29 patients with brain hemorrhage and 45 control patients with other neurological diseases. Fifteen patients with brain hemorrhage showed low cystatin C levels (less than or equal to 70 ng/ml) in a clinical setting in which the positive and negative findings were compatible with a diagnosis of cerebral amyloid angiopathy. Immunohistological examination of brain tissue obtained by biopsy from two of the 15 patients confirmed the diagnosis of cerebral amyloid angiopathy and identified the deposition of cystatin C and beta-protein. This enzyme-linked immunosorbent assay is simple to perform and may be useful for investigating patients suspected of having cerebral amyloid angiopathy with brain hemorrhage and the deposition of cystatin C.