Clinical and diagnostic implications of Alzheimer's disease copathology in Lewy body disease.

Concomitant Alzheimer's disease (AD) pathology is a frequent event in the context of Lewy body disease (LBD), occurring in approximately half of all cases. Evidence shows that LBD patients with AD copathology show an accelerated disease course, a greater risk of cognitive decline and an overall poorer prognosis. However, LBD-AD cases may show heterogeneous motor and non-motor phenotypes with a higher risk of dementia and, consequently, be not rarely misdiagnosed. In this review, we summarize the current understanding of LBD-AD by discussing the synergistic effects of AD neuropathological changes and Lewy pathology and their clinical relevance. Furthermore, we provide an extensive overview of neuroimaging and fluid biomarkers under assessment for use in LBD-AD and their possible diagnostic and prognostic values. AD pathology can be predicted in vivo by means of CSF, MRI and PET markers, whereas the most promising technique to date for identifying Lewy pathology in different biological tissues is the α-synuclein seed amplification assay. Pathological imaging and CSF AD biomarkers are associated with a higher likelihood of cognitive decline in LBD but do not always mirror the neuropathological severity as in pure AD. Implementing the use of blood-based AD biomarkers might allow faster screening of LBD patients for AD copathology, thus improving the overall diagnostic sensitivity for LBD-AD. Finally, we discuss the literature on novel candidate biomarkers being exploited in LBD-AD to investigate other aspects of neurodegeneration, such as neuroaxonal injury, glial activation and synaptic dysfunction. The thorough characterization of AD copathology in LBD should be taken into account when considering differential diagnoses of dementia syndromes, to allow prognostic evaluation on an individual level, and to guide symptomatic and disease-modifying therapies.

Safety and efficacy of concomitant treatment with non-vitamin K antagonist oral anticoagulants and antiseizure medications: A propensity score matching cohort study.

Research on cerebrovascular events in atrial fibrillation (AF) patients taking non-vitamin K antagonist oral anticoagulants (NOACs) with antiseizure medications (ASMs) is limited, highlighting a significant gap in literature. We assessed thrombotic and hemorrhagic risks in patients on NOACs and ASMs versus those on NOACs or ASMs alone. We analyzed a retrospective cohort from five centers, including AF and epilepsy patients on both medications (n = 188), AF patients on NOACs (n = 298), and epilepsy patients on ASMs (n = 50), with a 3-year follow-up. Propensity score matching adjusted for cardiovascular risk differences. The primary outcomes were ischemic stroke, transient ischemic attack, and major bleeding. Results showed the ASM+NOAC group had a higher risk of primary outcomes compared to the NOAC-only group (5.68% vs. 1.18%, hazard ratio = 5.72, 95% confidence interval = 2.22-14.73), with no events in the ASM-only group. This suggests an increased risk for patients on combined NOAC and ASM therapy, underlining the need for careful drug interaction consideration.

CSF and plasma Aß42/40 across Alzheimer's disease continuum: comparison of two ultrasensitive Simoa® assays targeting distinct amyloid regions.

OBJECTIVES: Decreased cerebrospinal fluid (CSF) amyloid beta 42/40 ratio (Aß42/40) is one of the core Alzheimer's disease (AD) biomarkers. Measurement of Aß42/40 in plasma has also been proposed as a surrogate marker for amyloidosis, however the validity and the diagnostic performance of this biomarker is still uncertain. Here we evaluated two immunoassays targeting distinct regions of the amyloid peptides by (a) performing a method comparison in both CSF and plasma, and (b) assessing the diagnostic performance across the AD continuum. METHODS: We used N4PE and N3PA Simoa® assays to measure Aß42/40 in CSF and plasma of 134 patients: preclinical AD (pre-AD, n=19), mild cognitive impairment due to AD (MCI-AD, n=41), AD at the dementia stage (AD-dem, n=35), and a control group (CTRL, n=39). The N4PE includes a detector antibody targeting the amyloid N-terminus, while the N3PA uses a detector targeting amyloid mid-region. RESULTS: Method comparison of N4PE and N3PA assays revealed discrepancies in assessment of plasma Aß42/Aß40. While the diagnostic performance of the two assays did not significantly differ in CSF, in plasma, N4PE assay provided better accuracy for AD discrimination than N3PA assay (AUC AD-dem vs. CTRL 0.77 N4PE, 0.68 N3PA). CONCLUSIONS: While both Aß42/40 assays allowed for an effective discrimination between CTRL and different AD stages, the assay targeting amyloid N-terminal region provided the best diagnostic performance in plasma. Differences observed in technical and diagnostic performance of the two assays may depend on matrix-specific amyloid processing, suggesting that further studies should be carried to standardize amyloid ratio measurement in plasma.

Hyposmia correlates with axial signs and gait disorder in Parkinson's disease: an Italian Olfactory Identification Test study.

BACKGROUND: Olfactory dysfunction is a non-motor symptom and an important biomarker of Parkinson's disease (PD) because of its high prevalence (> 90%). Whether hyposmia correlates with motor symptoms is unclear. In the present study, we aim to investigate the relationship between olfactory impairment with both motor and non-motor features and disease variables (disease duration, stage, and severity). METHODS: One-hundred fifty-four PD patients were evaluated. Odor identification ability was tested using Italian Olfactory Identification Test (IOIT). A comprehensive spectrum of motor and non-motor features was assessed. Cognitive function was investigated through MMSE. Patients were divided into 3 different clinical phenotypes using UPDRS-III: tremor-dominant type (TDT), akinetic-rigid type (ART), and mixed type (MXT). RESULTS: Three of the 33 IOIT items were most frequently misidentified: basil (74.3%), coffee (66.9%), and mushroom (59.6%). Hyposmia was found in 93%. Hyposmic patients were older than controls (p = 0.01). Hoehn & Yahr (H&Y) score of 2 or greater was associated with higher probability of being hyposmic (OR = 5.2, p = 0.01). IOIT score did not significantly differ between TDT, ART, and MXT of analyzed PD patients. Performance to IOIT inversely correlated with age (p < 0.01), disease duration (p = 0.01), and H&Y score of 2 or higher (p < 0.01). Clinical features that associated with higher IOIT score were freezing of gait (FOG) (p < 0.001) and camptocormia (p < 0.05). CONCLUSIONS: In our cohort, IOIT scores showed a positive correlation with axial motor signs, but not with non-motor symptoms. IOIT may be a useful tool not only for supporting PD diagnosis but also for providing prognostic information about motor function.

Investigating alpha-synuclein co-pathology in Alzheimer's disease by means of cerebrospinal fluid alpha-synuclein seed amplification assay.

INTRODUCTION: Lewy body disease, a frequently observed co-pathology in Alzheimer's disease (AD), can be identified antemortem in cerebrospinal fluid (CSF) by α-synuclein seed amplification assay (αS-SAA). The prevalence and clinical impact of CSF αS-SAA positivity in AD are still unknown. METHODS: αS-SAA was performed on CSF samples from 240 AD patients (preclinical, prodromal, and dementia stages), 85 controls, 84 patients with Parkinson's disease (PD), and 21 patients with PD with dementia or dementia with Lewy bodies. In AD patients, associations between αS-SAA positivity and cognitive changes were also evaluated. RESULTS: In agreement with available neuropathological studies, αS-SAA positivity was observed in 30% of AD patients (vs 9% in controls), and was associated with cognitive decline, visuospatial impairment, and behavioral disturbances. DISCUSSION: αS-SAA positivity in AD patients reflects the prevalence observed in neuropathological series and is associated with a worse clinical outcome. These data confirm the validity of CSF αS-SAA positivity as biomarker of synucleinopathy.

Fully automated measurement of plasma Aß42/40 and p-tau181: Analytical robustness and concordance with cerebrospinal fluid profile along the Alzheimer's disease continuum in two independent cohorts.

INTRODUCTION: For routine clinical implementation of Alzheimer's disease (AD) plasma biomarkers, fully automated random-access platforms are crucial to ensure reproducible measurements. We aimed to perform an analytical validation and to establish cutoffs for AD plasma biomarkers measured with Lumipulse. METHODS: Two cohorts were included. UNIPG: n = 450 paired cerebrospinal fluid (CSF)/plasma samples from subjects along the AD-continuum, subjects affected by other neurodegenerative diseases, and controls with known CSF profile; AMS: n = 40 plasma samples from AD and n = 40 controls. Plasma amyloid ß (Aß)42, Aß40, and p-tau181 were measured with Lumipulse. We evaluated analytical and diagnostic performance. RESULTS: Lumipulse assays showed high analytical performance. Plasma p-tau181 levels accurately reflected CSF A+/T+ profile in AD-dementia and mild cognitive impairment (MCI)-AD, but not in asymptomatic-AD. Plasma and CSF Aß42/40 values were concordant across clinical AD stages. Cutoffs and probability-based models performed satisfactorily in both cohorts. DISCUSSION: The identified cutoffs and probability-based models represent a significant step toward plasma AD molecular diagnosis.

Trajectories of CSF and plasma biomarkers across Alzheimer's disease continuum: disease staging by NF-L, p-tau181, and GFAP.

CSF-to-plasma transition will open new avenues for molecular phenotyping of Alzheimer's disease (AD). Here we evaluated a panel of AD biomarkers in matched CSF and plasma samples across the AD continuum, from preclinical AD to dementia. The aims were to: 1) compare diagnostic performance of the two biofluids, 2) evaluate trajectories of the biomarkers along AD progression. We analyzed CSF and plasma Aß42/40, p-tau181, p-tau231, t-tau, NF-L, GFAP, UCHL-1 and CSF SNAP-25 in a cohort (n = 173) of preclinical AD, MCI-AD, AD dementia, frontotemporal dementia patients, and controls. We found a significant correlation between CSF and plasma levels of Aß42/40, p-tau181, p-tau231, NF-L, and GFAP, while no CSF-plasma correlation was observed for t-tau and UCHL-1. Next to the core CSF biomarkers (Aß42/40, p-tau181, t-tau), those providing the best discrimination between controls and preclinical AD were CSF p-tau231 and SNAP-25 and plasma Aß42/40, p-tau231, and GFAP. Among plasma biomarkers, we found Aß42/Aß40, GFAP, and p-tau231 to show the largest rate of change at the CSF biomarker-defined cut-offs for amyloidosis and tauopathy. Finally, we identified GFAP, NF-L, and p-tau181 as the biomarkers most significantly associated with disease progression in both CSF and plasma. We suggest that a well-standardized and validated panel of selected plasma markers can facilitate early AD diagnosis, even at the asymptomatic disease stage. We propose that both CSF and plasma measurement of NF-L, p-tau181, and GFAP may play a significant role in disease staging and monitoring.

Psychiatric symptoms in multiple sclerosis: a biological perspective on synaptic and network dysfunction.

Psychiatric symptoms frequently occur in multiple sclerosis (MS), presenting with a complex phenomenology that encompasses a large clinical spectrum from clear-cut psychiatric disorders up to isolated psychopathological manifestations. Despite their relevant impact on the overall disease burden, such clinical features are often misdiagnosed, receive suboptimal treatment and are not systematically evaluated in the quantification of disease activity. The development of psychiatric symptoms in MS underpins a complex pathogenesis involving both emotional reactions to a disabling disease and structural multifocal central nervous system damage. Here, we review MS psychopathological manifestations under a biological perspective, highlighting the pathogenic relevance of synaptic and neural network dysfunction. Evidence obtained from human and experimental disease models suggests that MS-related psychiatric phenomenology is part of a disconnection syndrome due to diffuse inflammatory and neurodegenerative brain damage.

Cerebrospinal fluid ß-synuclein as a synaptic biomarker for preclinical Alzheimer's disease.

INTRODUCTION: ß-synuclein (ß-syn) is a presynaptic protein, whose cerebrospinal fluid (CSF) levels are increased in patients with Alzheimer's diseases (AD) showing mild cognitive impairment (MCI) and dementia (dem). Here, we aimed to investigate CSF ß-syn in subjects at different AD stages, including preclinical AD (pre-AD), and to compare its behaviour with another synaptic biomarker, α-synuclein (α-syn), and two biomarkers of neuro-axonal damage, namely neurofilament light chain protein (NfL) and total tau protein (t-tau). METHODS: We measured ß-syn, α-syn, t-tau and NfL in CSF of 75 patients with AD (pre-AD n=17, MCI-AD n=28, dem-AD n=30) and 35 controls (subjective memory complaints, SMC-Ctrl n=13, non-degenerative neurological disorders, Dis-Ctrl n=22). RESULTS: CSF ß-syn, α-syn, t-tau were significantly elevated in pre-AD patients compared with controls (p<0.0001, p=0.02 and p=0.0001, respectively), while NfL only increased in dem-AD (p=0.001). Pre-AD cases showed lower t-tau concentrations than MCI-AD (p=0.04) and dem-AD (p=0.01). CSF ß-syn had the best diagnostic performance for the discrimination of pre-AD subjects from all controls (area under the curve, AUC=0.97) and from SMC-Ctrl subjects (AUC=0.99). DISCUSSION: CSF ß-syn increases in the whole AD continuum since the preclinical stage and represents a promising biomarker of synaptic damage in AD.

LRRK2 Quantification in Cerebrospinal Fluid of Patients with Parkinson's Disease and Atypical Parkinsonian Syndromes.

BACKGROUND: The alteration of leucine-rich repeat kinase 2 (LRRK2) kinase activity is thought to be involved in Parkinson's disease (PD) pathogenesis beyond familiar cases, and LRRK2 inhibitors are currently under investigation. Preliminary data suggest a relationship between LRRK2 alteration and cognitive impairment in PD. OBJECTIVE: To investigate cerebrospinal fluid (CSF) LRRK2 levels in PD and other parkinsonian disorders, also correlating them with cognitive impairment. METHODS: In this study, we retrospectively investigated by means of a novel highly sensitive immunoassay the levels of total and phosphorylated (pS1292) LRRK2 in CSF of cognitively unimpaired PD (n = 55), PD with mild cognitive impairment (n = 49), PD with dementia (n = 18), dementia with Lewy bodies (n = 12), atypical parkinsonian syndromes (n = 35), and neurological controls (n = 30). RESULTS: Total and pS1292 LRRK2 levels were significantly higher in PD with dementia with respect to PD with mild cognitive impairment and PD, and also showed a correlation with cognitive performances. CONCLUSIONS: The tested immunoassay may represent a reliable method for assessing CSF LRRK2 levels. The results appear to confirm an association of LRRK2 alteration with cognitive impairment in PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The Immune Signature of CSF in Multiple Sclerosis with and without Oligoclonal Bands: A Machine Learning Approach to Proximity Extension Assay Analysis.

Early diagnosis of multiple sclerosis (MS) relies on clinical evaluation, magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) analysis. Reliable biomarkers are needed to differentiate MS from other neurological conditions and to define the underlying pathogenesis. This study aimed to comprehensively profile immune activation biomarkers in the CSF of individuals with MS and explore distinct signatures between MS with and without oligoclonal bands (OCB). A total of 118 subjects, including relapsing-remitting MS with OCB (MS OCB+) (n = 58), without OCB (MS OCB-) (n = 24), and controls with other neurological diseases (OND) (n = 36), were included. CSF samples were analyzed by means of proximity extension assay (PEA) for quantifying 92 immune-related proteins. Neurofilament light chain (NfL), a marker of axonal damage, was also measured. Machine learning techniques were employed to identify biomarker panels differentiating MS with and without OCB from controls. Analyses were performed by splitting the cohort into a training and a validation set. CSF CD5 and IL-12B exhibited the highest discriminatory power in differentiating MS from controls. CSF MIP-1-alpha, CD5, CXCL10, CCL23 and CXCL9 were positively correlated with NfL. Multivariate models were developed to distinguish MS OCB+ and MS OCB- from controls. The model for MS OCB+ included IL-12B, CD5, CX3CL1, FGF-19, CST5, MCP-1 (91% sensitivity and 94% specificity in the training set, 81% sensitivity, and 94% specificity in the validation set). The model for MS OCB- included CX3CL1, CD5, NfL, CCL4 and OPG (87% sensitivity and 80% specificity in the training set, 56% sensitivity and 48% specificity in the validation set). Comprehensive immune profiling of CSF biomarkers in MS revealed distinct pathophysiological signatures associated with OCB status. The identified biomarker panels, enriched in T cell activation markers and immune mediators, hold promise for improved diagnostic accuracy and insights into MS pathogenesis.

Alpha and Beta Synucleins: From Pathophysiology to Clinical Application as Biomarkers.

The synuclein family includes three neuronal proteins, named α-synuclein, ß-synuclein, and γ-synuclein, that have peculiar structural features. α-synuclein is largely known for being a key protein in the pathophysiology of Parkinson's disease (PD) and other synucleinopathies, namely, dementia with Lewy bodies and multisystem atrophy. The role of ß-synuclein and γ-synuclein is less well understood in terms of physiological functions and potential contribution to human diseases. α-synuclein has been investigated extensively in both cerebrospinal fluid (CSF) and blood as a potential biomarker for synucleinopathies. Recently, great attention has been also paid to ß-synuclein, whose CSF and blood levels seem to reflect synaptic damage and neurodegeneration independent of the presence of synucleinopathy. In this review, we aim to provide an overview on the pathophysiological roles of the synucleins. Because γ-synuclein has been poorly investigated in the field of synucleinopathy and its pathophysiological roles are far from being clear, we focus on the interactions between α-synuclein and ß-synuclein in PD. We also discuss the role of α-synuclein and ß-synuclein as potential biomarkers to improve the diagnostic characterization of synucleinopathies, thus highlighting their potential application in clinical trials for disease-modifying therapies. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

PEG-J replacement for duodenal levodopa infusion in Parkinson's disease patients: a retrospective study.

BACKGROUND: Reducing percutaneous endoscopic gastrostomies with jejunal extension tubes (PEG-J) related complications is vital to the long-term preservation of duodenal levodopa infusion (DLI) in advanced Parkinson's disease (APD). Here, we provide data on the frequency of complications for both the standard "pull" and the non-endoscopic, radiologic assisted, "push" replacement PEG-J techniques in APD. METHODS: We retrospectively identified all patients treated with DLI from October 2009 to January 2020 at the Movement Disorders Center. Patients features and demographics, PEG-J procedures, causes for any discontinuation, reported complications and mortality were collected. In this cohort, PEG-J replacements were performed using the standard "pull" procedure or the radiologic assisted "push" method. Descriptive statistical analysis, t-test and paired t-test with False Discovery Rate correction was performed. RESULTS: This retrospective study included 30 APD patients [median age 72 ± 5.6 years; mean disease duration 17.2 + 5.7 years]. Mean treatment duration was 35.6 (30.6) months. Overall, 156 PEG-J procedures were performed, and Nineteen patients (63.3%) had a total of 185 reported complications, 85 of which were peristomal complications. 17 (56.6%) underwent 100 replacement procedures due to complications. The most commonly reported complication for replacement was J-tube dislocation (36%). One patient discontinued treatment after 6 months, due to peripheral neuropathy. Six patients died for causes not related to DLI. PEG-J replacements performed with the "push" method had a higher turnover (5.6 vs. 7.6 mo.), but fewer reported complications (67 vs. 75%). CONCLUSION: The overall rate of complications was lower for "push" technique. This result might have been due to a higher replacement turnover that acted as a protective factor.

Validation of the LUMIPULSE automated immunoassay for the measurement of core AD biomarkers in cerebrospinal fluid.

OBJECTIVES: The core cerebrospinal fluid (CSF) biomarkers; total tau (tTau), phospho-tau (pTau), amyloid ß 1-42 (Aß 1-42), and the Aß 1-42/Aß 1-40 ratio have transformed Alzheimer's disease (AD) research and are today increasingly used in clinical routine laboratories as diagnostic tools. Fully automated immunoassay instruments with ready-to-use assay kits and calibrators has simplified their analysis and improved reproducibility of measurements. We evaluated the analytical performance of the fully automated immunoassay instrument LUMIPULSE G (Fujirebio) for measurement of the four core AD CSF biomarkers and determined cutpoints for AD diagnosis. METHODS: Comparison of the LUMIPULSE G assays was performed with the established INNOTEST ELISAs (Fujirebio) for hTau Ag, pTau 181, ß-amyloid 1-42, and with V-PLEX Plus Aß Peptide Panel 1 (6E10) (Meso Scale Discovery) for Aß 1-42/Aß 1-40, as well as with a LC-MS reference method for Aß 1-42. Intra- and inter-laboratory reproducibility was evaluated for all assays. Clinical cutpoints for Aß 1-42, tTau, and pTau was determined by analysis of three cohorts of clinically diagnosed patients, comprising 651 CSF samples. For the Aß 1-42/Aß 1-40 ratio, the cutpoint was determined by mixture model analysis of 2,782 CSF samples. RESULTS: The LUMIPULSE G assays showed strong correlation to all other immunoassays (r>0.93 for all assays). The repeatability (intra-laboratory) CVs ranged between 2.0 and 5.6%, with the highest variation observed for ß-amyloid 1-40. The reproducibility (inter-laboratory) CVs ranged between 2.1 and 6.5%, with the highest variation observed for ß-amyloid 1-42. The clinical cutpoints for AD were determined to be 409 ng/L for total tau, 50.2 ng/L for pTau 181, 526 ng/L for ß-amyloid 1-42, and 0.072 for the Aß 1-42/Aß 1-40 ratio. CONCLUSIONS: Our results suggest that the LUMIPULSE G assays for the CSF AD biomarkers are fit for purpose in clinical laboratory practice. Further, they corroborate earlier presented reference limits for the biomarkers.

Accuracy of the clinical diagnosis of dementia with Lewy bodies (DLB) among the Italian Dementia Centers: a study by the Italian DLB study group (DLB-SINdem).

INTRODUCTION: Dementia with Lewy bodies (DLB) may represent a diagnostic challenge, since its clinical picture overlaps with other dementia. Two toolkits have been developed to aid the clinician to diagnose DLB: the Lewy Body Composite Risk Score (LBCRS) and the Assessment Toolkit for DLB (AT-DLB). We aim to evaluate the reliability of these two questionnaires, and their ability to enhance the interpretation of the international consensus diagnostic criteria. METHODS: LBCRS and AT-DLB were distributed to 135 Italian Neurological Centers for Cognitive Decline and Dementia (CDCDs), with the indication to administer them to all patients with dementia referred within the subsequent 3 months. We asked to subsequently apply consensus criteria for DLB diagnosis, to validate the diagnostic accuracy of the two toolkits. RESULTS: A total of 23 Centers joined the study; 1854 patients were enrolled. We found a prevalence of possible or probable DLB of 13% each (26% total), according to the consensus criteria. LBCRS toolkit showed good reliability, with a Cronbach alpha of 0.77, stable even after removing variables from the construct. AT-DLB toolkit Cronbach alpha was 0.52 and, after the subtraction of the "cognitive fluctuation" criterion, was only 0.31. Accuracy, sensitivity, and specificity were higher for LBCRS vs. AT-DLB. However, when simultaneously considered in the logistic models, AT-DLB showed a better performance (p < 0.001). Overall, the concordance between LBCRS positive and AT-DLB possible/probable was of 78.02% CONCLUSIONS: In a clinical setting, the LBCRS and AT-DLB questionnaires have good accuracy for DLB diagnosis.

Characteristics of subjective cognitive decline associated with amyloid positivity.

INTRODUCTION: The evidence for characteristics of persons with subjective cognitive decline (SCD) associated with amyloid positivity is limited. METHODS: In 1640 persons with SCD from 20 Amyloid Biomarker Study cohort, we investigated the associations of SCD-specific characteristics (informant confirmation, domain-specific complaints, concerns, feelings of worse performance) demographics, setting, apolipoprotein E gene (APOE) ε4 carriership, and neuropsychiatric symptoms with amyloid positivity. RESULTS: Between cohorts, amyloid positivity in 70-year-olds varied from 10% to 76%. Only older age, clinical setting, and APOE ε4 carriership showed univariate associations with increased amyloid positivity. After adjusting for these, lower education was also associated with increased amyloid positivity. Only within a research setting, informant-confirmed complaints, memory complaints, attention/concentration complaints, and no depressive symptoms were associated with increased amyloid positivity. Feelings of worse performance were associated with less amyloid positivity at younger ages and more at older ages. DISCUSSION: Next to age, setting, and APOE ε4 carriership, SCD-specific characteristics may facilitate the identification of amyloid-positive individuals.

Clinical reporting following the quantification of cerebrospinal fluid biomarkers in Alzheimer's disease: An international overview.

INTRODUCTION: The current practice of quantifying cerebrospinal fluid (CSF) biomarkers as an aid in the diagnosis of Alzheimer's disease (AD) varies from center to center. For a same biochemical profile, interpretation and reporting of results may differ, which can lead to misunderstandings and raises questions about the commutability of tests. METHODS: We obtained a description of (pre-)analytical protocols and sample reports from 40 centers worldwide. A consensus approach allowed us to propose harmonized comments corresponding to the different CSF biomarker profiles observed in patients. RESULTS: The (pre-)analytical procedures were similar between centers. There was considerable heterogeneity in cutoff definitions and report comments. We therefore identified and selected by consensus the most accurate and informative comments regarding the interpretation of CSF biomarkers in the context of AD diagnosis. DISCUSSION: This is the first time that harmonized reports are proposed across worldwide specialized laboratories involved in the biochemical diagnosis of AD.

Specific Cerebrospinal Fluid SerpinA1 Isoform Pattern in Alzheimer's Disease.

SerpinA1 (α1-antitrypsin) is a soluble glycoprotein, the cerebrospinal fluid (CSF) isoforms of which showed disease-specific changes in neurodegenerative disorders that are still unexplored in Alz-heimer's disease (AD). By means of capillary isoelectric focusing immunoassay, we investigated six serpinA1 isoforms in CSF samples of controls (n = 29), AD-MCI (n = 29), AD-dem (n = 26) and Lewy body disease (LBD, n = 59) patients and correlated the findings with CSF AD core biomarkers (Aß42/40 ratio, p-tau, t-tau). Four CSF serpinA1 isoforms were differently expressed in AD patients compared to controls and LBD patients, especially isoforms 2 and 4. AD-specific changes were found since the MCI stage and significantly correlated with decreased Aß42/40 (p < 0.05) and in-creased p-tau and t-tau levels in CSF (p < 0.001). Analysis of serpinA1 isoform provided good di-agnostic accuracy in discriminating AD patients versus controls (AUC = 0.80) and versus LBD patients (AUC = 0.92), with best results in patients in the dementia stage (AUC = 0.97). SerpinA1 isoform expression is altered in AD patients, suggesting a common, albeit disease-specific, in-volvement of serpinA1 in most neurodegenerative disorders.

High performance liquid chromatography determination of L-glutamate, L-glutamine and glycine content in brain, cerebrospinal fluid and blood serum of patients affected by Alzheimer's disease.

Altered glutamatergic neurotransmission is thought to play a crucial role in the progression of Alzheimer's disease (AD). Accordingly, the identification of peculiar biochemical patterns reflecting AD-related synaptopathy in blood and cerebrospinal fluid (CSF) could have relevant diagnostic and prognostic implications. In this study, we measured by High-Performance Liquid Chromatography the amount of glutamate, glutamine and glycine in post-mortem brain samples of AD patients, as well as in CSF and blood serum of drug-free subjects encompassing the whole AD clinical spectrum (pre-clinical AD, n = 18, mild cognitive impairment-AD, n = 29, dementia AD, n = 30). Interestingly, we found that glutamate and glycine levels, as well as total tau protein content, were significantly reduced in the superior frontal gyrus of patients with AD, compared with non-demented controls. No significant change was also found in glutamate, glutamine and glycine CSF concentrations between AD patients and neurological controls. Remarkably, serum glutamate levels were significantly higher in patients affected by early AD phases compared to controls, and were negatively correlated with CSF total tau levels. Conversely, serum glutamine concentration was significantly increased in AD patients, with a negative correlation with MMSE performances. Finally, we reported a significant correlation between serum L-glutamate concentrations and CDR score in female but not in male cohort of AD subjects. Overall, our results suggest that serum glutamate and glutamine levels in AD patients could vary across disease stages, potentially reflecting the progressive alteration of glutamatergic signaling during neurodegenerative processes.

Novel noninvasive biomarkers of prodromal Alzheimer disease: The role of optical coherence tomography and optical coherence tomography-angiography.

BACKGROUND AND PURPOSE: A reduction of retinal thickness and an alteration of retinal perfusion have been found in Alzheimer disease (AD). Nowadays, retinal layers and retinal perfusion can be evaluated by means of noninvasive imaging techniques, namely, optical coherence tomography (OCT) and OCT-angiography (OCT-A). Here, we have compared the retinal thickness and the perfusion index, measured by means of OCT and OCT-A, in patients with mild cognitive impairment due to AD (MCI-AD) and in age- and sex-matched cognitively healthy controls. METHODS: Twenty-four MCI-AD patients and 13 control subjects were enrolled. MCI-AD patients underwent lumbar puncture; all of them showed a cerebrospinal fluid (CSF) profile compatible with AD. OCT was used for evaluating retinal volumes and thicknesses, whereas with OCT-A we measured fractal dimension (FD), vascular perfusion density (VPD), and vessel length density (VLD) of superficial capillary plexus (SCP), intermediate capillary plexus (ICP), deep capillary plexus (DCP), and choriocapillaris. The comparisons between groups were made after adjustment for age, diabetes, and hypertension. RESULTS: A significant reduction of SCP-VLD (p = 0.012), ICP-VPD (p = 0.015), ICP-VLD (p = 0.004), DCP-VPD (p = 0.012), and DCP-VLD (p = 0.009) was found in MCI-AD patients compared to controls. Conversely, FD was higher in MCI-AD than in controls (p = 0.044). CSF Aß42/total tau negatively correlated with FD (r = -0.51, p = 0.010). CONCLUSIONS: OCT-A might have a potential role in detecting new noninvasive biomarkers for early AD detection. Retinal VPD might identify amyloid angiopathy-related chronic injury, and FD could show early vessel recruitment as a compensative mechanism at disease onset. Further studies will be needed to confirm these findings.