Fluid Candidate Biomarkers for Alzheimer's Disease: A Precision Medicine Approach

A plethora of dynamic pathophysiological mechanisms underpins highly heterogeneous phenotypes in the field of dementia, particularly in Alzheimer's disease (AD). In such a faceted scenario, a biomarker-guided approach, through the implementation of specific fluid biomarkers individually reflecting distinct molecular pathways in the brain, may help establish a proper clinical diagnosis, even in its preclinical stages. Recently, ultrasensitive assays may detect different neurodegenerative mechanisms in blood earlier. ß-amyloid (Aß) peptides, phosphorylated-tau (p-tau), and neurofilament light chain (NFL) measured in blood are gaining momentum as candidate biomarkers for AD. P-tau is currently the more convincing plasma biomarker for the diagnostic workup of AD. The clinical role of plasma Aβ peptides should be better elucidated with further studies that also compare the accuracy of the different ultrasensitive techniques. Blood NFL is promising as a proxy of neurodegeneration process tout court. Protein misfolding amplification assays can accurately detect α-synuclein in cerebrospinal fluid (CSF), thus representing advancement in the pathologic stratification of AD. In CSF, neurogranin and YKL-40 are further candidate biomarkers tracking synaptic disruption and neuroinflammation, which are additional key pathophysiological pathways related to AD genesis. Advanced statistical analysis using clinical scores and biomarker data to bring together individuals with AD from large heterogeneous cohorts into consistent clusters may promote the discovery of pathophysiological causes and detection of tailored treatments

EFAS/EAN survey on the influence of the COVID-19 pandemic on European clinical autonomic education and research

© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.Purpose: To understand the influence of the coronavirus disease 2019 (COVID-19) pandemic on clinical autonomic education and research in Europe. Methods: We invited 84 European autonomic centers to complete an online survey, recorded the pre-pandemic-to-pandemic percentage of junior participants in the annual congresses of the European Federation of Autonomic Societies (EFAS) and European Academy of Neurology (EAN) and the pre-pandemic-to-pandemic number of PubMed publications on neurological disorders. Results: Forty-six centers answered the survey (55%). Twenty-nine centers were involved in clinical autonomic education and experienced pandemic-related didactic interruptions for 9 (5; 9) months. Ninety percent (n = 26/29) of autonomic educational centers reported a negative impact of the COVID-19 pandemic on education quality, and 93% (n = 27/29) established e-learning models. Both the 2020 joint EAN-EFAS virtual congress and the 2021 (virtual) and 2022 (hybrid) EFAS and EAN congresses marked higher percentages of junior participants than in 2019. Forty-one respondents (89%) were autonomic researchers, and 29 of them reported pandemic-related trial interruptions for 5 (2; 9) months. Since the pandemic begin, almost half of the respondents had less time for scientific writing. Likewise, the number of PubMed publications on autonomic topics showed the smallest increase compared with other neurological fields in 2020-2021 and the highest drop in 2022. Autonomic research centers that amended their trial protocols for telemedicine (38%, n = 16/41) maintained higher clinical caseloads during the first pandemic year. Conclusions: The COVID-19 pandemic had a substantial negative impact on European clinical autonomic education and research. At the same time, it promoted digitalization, favoring more equitable access to autonomic education and improved trial design.info:eu-repo/semantics/publishedVersio

Valutazione della struttura della sostanza nera nei pazienti con disturbo comportamentale del sonno REM: evidenze da uno studio in risonanza magnetica ad ultra-alto campo

Nell’ambito della storia naturale dei parkinsonismi degenerativi si identificano una lunga fase asintomatica, in cui il processo neurodegenerativo è in atto ma non si hanno manifestazioni cliniche, una fase prodromica, caratterizzata da segni e sintomi (per lo più non motori) che non soddisfano i criteri diagnostici per parkinsonismo ed una fase di malattia clinicamente conclamata. Il disturbo comportamentale del sonno REM (RBD) rientra nella possibile gamma di manifestazioni non motorie con cui possono esprimersi clinicamente, anche molto precocemente, i parkinsonismi degenerativi. Oltre che sintomo non motorio il disturbo comportamentale del sonno REM è anche un sintomo pre-motorio o prodromico di malattia, la cui comparsa può precorrere anche di diversi anni la diagnosi formale di parkinsonismo degenerativo formulata secondo i criteri diagnostici correnti. Obiettivo del presente studio è la ricerca e la caratterizzazione, nei pazienti con disturbo comportamentale del sonno REM idiopatico (iRBD), di alterazioni strutturali a carico della sostanza nera, già descritte nei pazienti con parkinsonismo idiopatico ed espressione di processo neurodegenerativo in atto a livello nigrale. A tale scopo sono stati reclutati 15 soggetti con diagnosi polisonnografica di iRBD (età media 69,3 ± 7,0 anni), 28 soggetti con Malattia di Parkinson clinicamente definita e confermata da scintigrafia con (123)-I-FP-CIT (età media 59,1 ± 9,1anni) e 14 controlli sani (età media 57,1 ± 7,0 anni). I soggetti reclutati sono stati sottoposti ad un’indagine di risonanza magnetica ad ultra-alto campo (7T). I soggetti con iRBD sono stati reclutati tra coloro che avessero effettuato nei tre mesi precedenti un’indagine funzionale di tipo scintigrafico (scintigrafia con (123)I-FP-CIT) allo scopo di valutare la concordanza tra i reperti morfologici (RM) e funzionali (scintigrafici). I dati emersi hanno evidenziato nel 60% dei pazienti con iRBD alterazioni morfologiche della sostanza nera compatibili con degenerazione nigrale e alterazioni del segnale scintigrafico nel 60% dei soggetti reclutati, con una concordanza osservata tra il reperto di risonanza e quello scintigrafico del 86,67% (K = 0,722). In conclusione, le evidenze raccolte sembrano rafforzare l’ipotesi di un possibile ruolo dello studio in risonanza magnetica della sostanza nera nella stratificazione dei soggetti con potenziali sintomi premotori, sulla base del rischio di sviluppare parkinsonismo degenerativo. Questo, anche alla luce dei recenti Criteri di ricerca per la diagnosi di Malattia di Parkinson in fase prodromica (Berg D et al., 2015) potrebbe rappresentare un utile e affidabile marcatore di parkinsonismo degenerativo prodromico. Sebbene l’elevata concordanza con l’esame scintigrafico supporti questa ipotesi sarà necessaria la valutazione prospettica dei pazienti con iRBD per verificare il rischio di conversione clinica motoria in coloro che mostrano alterazioni della sostanza nera nell’esame di risonanza magnetica

Relationship between cardiovascular autonomic failure and cognitive performance in the ?-synucleinopathies: preliminary cross-sectional analysis of the Natural History Study of Synucleinopathies (NHSS) registry

Cardiovascular autonomic failure, presenting with neurogenic orthostatic hypotension (nOH) and supine hypertension (SH), is a common non-motor feature of the α-synucleinopathies. High blood pressure (BP) variability may foster end-organ damage and promote cognitive impairment. Nevertheless, the interplay between cardiovascular dysautonomia and cognitive performance in α-synucleinopathies is yet unclear. We therefore analyzed data from 76 Parkinson´s Disease (PD), 282 Multiple System Atrophy (MSA) and 133 stable pure autonomic failure (PAF) patients enrolled in the Natural History Study of Synucleinopathies (NHSS). The Montreal Cognitive Assessment (MoCA) was used to test patients’ baseline cognitive performance. Orthostatic hypotension (OH), neurogenic OH (nOH) and SH were defined based on supine-to-standing heart rate and BP measurements contemporary to cognitive testing. In PD, 36% of patients (n=26) had no OH, 15% (n=11) non-neurogenic OH, 11% (n=8) nOH and 38% (n=28) both nOH and SH. In PAF 8% of patients (n=9) showed no OH, 21% (n=24) non-neurogenic OH, 12% (n=14) nOH and 58% (n=66) both nOH and SH. In MSA, 25% of patients (n=65) had no OH, 17% (n=45) non-neurogenic OH, 16% (n=43) nOH and 42% (n=114) both nOH and SH. In our cross-sectional analysis, median MoCA scores did not differ across PD (p=0.108) and PAF (p=0.453) patients with and without baseline orthostatic BP dysregulation. In MSA, the nOH subgroup showed higher median MoCA scores (p=0.036) compared to the other groups but different clinical-demographic features may account for this observation. The longitudinal analysis of MoCA score changes according to baseline BP dysregulation will clarify the impact of cardiovascular dysautonomia on the progression of cognitive impairment in the α-synucleinopathies

The role of synaptic biomarkers in the spectrum of neurodegenerative diseases

Introduction: The quest for reliable fluid biomarkers tracking synaptic disruption is supported by the evidence of a tight association between synaptic density and cognitive performance in neurodegenerative diseases (NDD), especially Alzheimer's disease (AD). Areas covered: Neurogranin (Ng) is a post-synaptic protein largely expressed in neurons involved in the memory networks. Currently, Ng measured in CSF is the most promising synaptic biomarker. Several studies show Ng elevated in AD dementia with a hippocampal phenotype as well as in MCI individuals who progress to AD. Ng concentrations are also increased in Creutzfeldt Jacob Disease where widespread and massive synaptic disintegration takes place. Ng does not discriminate Parkinson's disease from atypical parkinsonisms, nor is it altered in Huntington disease. CSF synaptosomal-associated protein 25 (SNAP-25) and synaptotagmin-1 (SYT-1) are emerging candidates. Expert opinion: CSF Ng revealed a role as a diagnostic and prognostic biomarker in NDD. Ng increase seems to be very specific for typical AD phenotype, probably for a prevalent hippocampal involvement. Synaptic biomarkers may serve different context-of-use in AD and other NDD including prognosis, diagnosis, and tracking synaptic damage - a critical pathophysiological mechanism in NDD - thus representing reliable tools for a precision medicine-oriented approach to NDD

Fluid Biomarkers in Alzheimer's Disease and Other Neurodegenerative Disorders: Toward Integrative Diagnostic Frameworks and Tailored Treatments

The diagnosis of neurodegenerative diseases (NDDs) represents an increasing social burden, with the unsolved issue of disease-modifying therapies (DMTs). The failure of clinical trials treating Alzheimer's Disease (AD) so far highlighted the need for a different approach in drug design and patient selection. Identifying subjects in the prodromal or early symptomatic phase is critical to slow down neurodegeneration, but the implementation of screening programs with this aim will have an ethical and social aftermath. Novel minimally invasive candidate biomarkers (derived from blood, saliva, olfactory brush) or classical cerebrospinal fluid (CSF) biomarkers have been developed in research settings to stratify patients with NDDs. Misfolded protein accumulation, neuroinflammation, and synaptic loss are the pathophysiological hallmarks detected by these biomarkers to refine diagnosis, prognosis, and target engagement of drugs in clinical trials. We reviewed fluid biomarkers of NDDs, considering their potential role as screening, diagnostic, or prognostic tool, and their present-day use in clinical trials (phase II and III). A special focus will be dedicated to novel techniques for the detection of misfolded proteins. Eventually, an applicative diagnostic algorithm will be proposed to translate the research data in clinical practice and select prodromal or early patients to be enrolled in the appropriate DMTs trials for NDDs

α-synuclein as an emerging pathophysiological biomarker of Alzheimer's disease

α-syn aggregates represent the pathological hallmark of synucleinopathies as well as a frequent copathology (almost 1/3 of cases) in AD. Recent research indicates a potential role of α-syn species, measured in CSF with conventional analytical techniques, in the differential diagnosis between AD and synucleinopathies (such as DLB). Pioneering studies report the detection of α-syn in blood, however, conclusive investigations are controversial. Ultrasensitive seed amplification techniques, enabling the selective quantification of α-syn seeds, may represent an effective solution to identify the α-syn component in AD and facilitate a biomarker-guided stratification

Progress regarding the context-of-use of tau as biomarker of Alzheimer's disease and other neurodegenerative diseases

INTRODUCTION: Tau protein misfolding and accumulation in toxic species is a critical pathophysiological process of Alzheimer's Disease (AD) and other neurodegenerative disorders (NDDs). Tau biomarkers, namely cerebrospinal fluid (CSF) total-tau (t-tau), 181-phosphorylated tau (p-tau) and tau-PET tracers, have been recently embedded in the diagnostic criteria for AD. Nevertheless, the role of tau as a diagnostic and prognostic biomarker for other NDDs remains controversial.AREAS COVERED: We performed a systematical PubMed-based review of the most recent advances in tau-related biomarkers for NDDs. We focused on papers published from 2015 to 2020 assessing the diagnostic or prognostic value of each biomarker.EXPERT OPINION: The assessment of tau biomarkers in alternative easily accessible matrices, through the development of ultrasensitive techniques, represents the most significant perspective for AD-biomarker research. In NDDs, novel tau isoforms (e.g., p-tau217) or proteolytic fragments (e.g., N-terminal fragments) may represent candidate diagnostic and prognostic biomarkers and may help monitoring disease progression. Protein misfolding amplification assays, allowing the identification of different tau strains (e.g. 3R- vs. 4R-tau) in CSF, may constitute a breakthrough for the in vivo stratification of NDDs. Tau-PET may help tracking the spatial-temporal evolution of tau pathophysiology in AD but its application outside the AD-spectrum deserves further studies