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 higher risk of dementia, and, consequently, be not rarely misdiagnosed. In this review, we summarize the state-of-the-art on LBD-AD by discussing the synergistic effects between AD neuropathological changes and Lewy pathology and their clinical relevance. Furthermore, we provide an extensive overview of neuroimaging and fluid biomarkers under assessment in LBD-AD and their possible diagnostic and prognostic value. AD pathology can be suspected in vivo by means of CSF, MRI and PET markers, whereas α-synuclein seed amplification assays (SAAs) represent to date the most promising technique to identify Lewy pathology in different biological tissues. 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 like in pure AD. The implementation of blood-based biomarkers of AD might allow the fast 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 for the differential diagnosis of dementia syndromes, for the prognostic evaluation on an individual level and for guiding symptomatic and disease-modifying therapies.

Methods to Discover and Validate Biofluid-Based Biomarkers in Neurodegenerative Dementias.

Neurodegenerative dementias are progressive diseases that cause neuronal network breakdown in different brain regions often because of accumulation of misfolded proteins in the brain extracellular matrix, such as amyloids or inside neurons or other cell types of the brain. Several diagnostic protein biomarkers in body fluids are being used and implemented, such as for Alzheimer's disease. However, there is still a lack of biomarkers for co-pathologies and other causes of dementia. Such biofluid-based biomarkers enable precision medicine approaches for diagnosis and treatment, allow to learn more about underlying disease processes, and facilitate the development of patient inclusion and evaluation tools in clinical trials. When designing studies to discover novel biofluid-based biomarkers, choice of technology is an important starting point. But there are so many technologies to choose among. To address this, we here review the technologies that are currently available in research settings and, in some cases, in clinical laboratory practice. This presents a form of lexicon on each technology addressing its use in research and clinics, its strengths and limitations, and a future perspective.

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.

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.

Modulation of Aß42 Aggregation Kinetics and Pathway by Low-Molecular-Weight Inhibitors.

The aggregation of amyloid-ß 42 (Aß42) is directly related to the pathogenesis of Alzheimer's disease. Here, we have investigated the early stages of the aggregation process, during which most of the cytotoxic species are formed. Aß42 aggregation kinetics, characterized by the quantification of Aß42 monomer consumption, were tracked by real-time solution NMR spectroscopy (RT-NMR) allowing the impact that low-molecular-weight (LMW) inhibitors and modulators exert on the aggregation process to be analysed. Distinct differences in the Aß42 kinetic profiles were apparent and were further investigated kinetically and structurally by using thioflavin T (ThT) and transmission electron microscopy (TEM), respectively. LMW inhibitors were shown to have a differential impact on early-state aggregation. Insight provided here could direct future therapeutic design based on kinetic profiling of the process of fibril formation.

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.

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.

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.

Cerebrospinal fluid hemoglobin levels as markers of blood contamination: relevance for α-synuclein measurement.

OBJECTIVES: Cerebrospinal fluid α-synuclein (CSF α-syn) represents a possible biomarker in Parkinson's disease (PD) diagnosis. CSF blood contamination can introduce a bias in α-syn measurement. To date, CSF samples with a red blood cells (RBC) count >50 RBC × 106/L or haemoglobin (Hb) concentration >200 µg/L are excluded from biomarker studies. However, investigations for defining reliable cut-off values are missing. METHODS: We evaluated the effect of blood contamination on CSF α-syn measurement by a systematic approach in a cohort of 42 patients with different neurological conditions who underwent lumbar puncture (LP) for diagnostic reasons. CSF samples were spiked with whole blood and serially diluted to 800, 400, 200, 100, 75, 50, 25, 5, 0 RBC × 106/L. CSF α-syn and Hb levels were measured by ELISA. RESULTS: In neat CSF, the average concentration of α-syn was 1,936 ± 636 ng/L. This value increased gradually in spiked CSF samples, up to 4,817 ± 1,456 ng/L (+149% α-syn variation) in samples with 800 RBC × 106/L. We established different cut-offs for discriminating samples with α-syn level above 5, 10, and 20% variation, corresponding to a Hb (RBC) concentration of 1,569 µg/L (37 RBC × 106/L), 2,082 µg/L (62 RBC × 106/L), and 3,118 µg/L (87 RBC × 106/L), respectively. CONCLUSIONS: Our data show the high impact of CSF blood contamination on CSF α-syn levels, highlighting the measurement of Hb concentration as mandatory when assessing CSF α-syn. The thresholds we calculated are useful to classify CSF samples for blood contamination, considering as reliable only those showing a Hb concentration <1,569 µg/L.

An Unbalanced Synaptic Transmission: Cause or Consequence of the Amyloid Oligomers Neurotoxicity?

Amyloid-ß (Aß) 1-40 and 1-42 peptides are key mediators of synaptic and cognitive dysfunction in Alzheimer's disease (AD). Whereas in AD, Aß is found to act as a pro-epileptogenic factor even before plaque formation, amyloid pathology has been detected among patients with epilepsy with increased risk of developing AD. Among Aß aggregated species, soluble oligomers are suggested to be responsible for most of Aß's toxic effects. Aß oligomers exert extracellular and intracellular toxicity through different mechanisms, including interaction with membrane receptors and the formation of ion-permeable channels in cellular membranes. These damages, linked to an unbalance between excitatory and inhibitory neurotransmission, often result in neuronal hyperexcitability and neural circuit dysfunction, which in turn increase Aß deposition and facilitate neurodegeneration, resulting in an Aß-driven vicious loop. In this review, we summarize the most representative literature on the effects that oligomeric Aß induces on synaptic dysfunction and network disorganization.

Multivariate Curve Resolution for 2D Solid-State NMR spectra.

We present a processing method, based on the multivariate curve resolution approach (MCR), to denoise 2D solid-state NMR spectra, yielding a substantial S/N ratio increase while preserving the lineshapes and relative signal intensities. These spectral features are particularly important in the quantification of silicon species, where sensitivity is limited by the low natural abundance of the 29Si nuclei and by the dilution of the intrinsic protons of silica, but can be of interest also when dealing with other intermediate-to-low receptivity nuclei. This method also offers the possibility of coprocessing multiple 2D spectra that have the signals at the same frequencies but with different intensities (e.g.: as a result of a variation in the mixing time). The processing can be carried out on the time-domain data, thus preserving the possibility of applying further processing to the data. As a demonstration, we have applied Cadzow denoising on the MCR-processed FIDs, achieving a further increase in the S/N ratio and more effective denoising also on the transients at longer indirect evolution times. We have applied the combined denoising on a set of experimental data from a lysozyme-silica composite.

The vicious cycle between α-synuclein aggregation and autophagic-lysosomal dysfunction.

The accumulation and misfolding of α-synuclein (α-syn) represent the main pathological hallmark of PD. Overexpression of α-syn and failure of cellular protein degradation systems play a major role in α-syn aggregation. The discovery of PD-associated genes related to the autophagic-lysosomal pathway, such as VPS35, LRRK2, GBA1, SMPD1, GALC, ASAH1, SCARB2, CTSD, CTSB, and GLA, confirms the involvement of cellular clearance systems dysfunction in PD pathogenesis. Of importance, lysosomal enzyme activity is altered both in genetic and sporadic PD. Decreased lysosomal enzymes activities were measured in the same brain regions where α-syn accumulates, suggesting that a crosstalk between α-syn aggregation and autophagic-lysosomal impairment may exist. The understanding of autophagic-lysosomal pathway dysfunctions' role in the pathogenesis and progression of synucleinopathies opened new perspectives for novel possible therapeutic strategies. In this article, the evidences and mechanisms of the reciprocal relation between autophagic-lysosomal pathway impairment and misfolded α-syn aggregation and propagation are reviewed, together with the most promising compounds targeting autophagic-lysosomal pathway restoration as a disease-modifying strategy for PD treatment. © 2019 International Parkinson and Movement Disorder Society.

CSF neurosecretory proteins VGF and neuroserpin in patients with Alzheimer's and Lewy body diseases.

BACKGROUND: VGF and neuroserpin are neurosecretory proteins involved in the pathophysiology of neurodegenerative diseases. We aimed to evaluate their cerebrospinal fluid (CSF) concentrations in patients with Alzheimer's disease (AD) and Lewy body disease (LBD). METHODS: We measured CSF VGF [AQEE] peptide and neuroserpin levels in 108 LBD patients, 76 AD patients and 37 controls, and tested their associations with clinical scores and CSF AD markers. RESULTS: We found decreased CSF levels of VGF [AQEE] in patients with LBD and dementia compared to controls (p = 0.016) and patients with AD-dementia (p = 0.011), but with significant influence of age and sex distribution. Moreover, we observed, on the one hand, a significant associations between lower VGF [AQEE] and neuroserpin levels and poorer cognitive performance (i.e., lower Mini-Mental State Examination scores). On the other hand, higher levels of CSF tau proteins, especially pTau181, were significantly associated with higher concentrations of VGF [AQEE] and neuroserpin. Indeed, LBD patients with AD-like CSF profiles, especially T+ profiles, had higher levels of VGF [AQEE] and neuroserpin compared to controls and LBD/T- cases. DISCUSSION: CSF VGF [AQEE] and neuroserpin may show a complex relationship with cognitive decline when the levels are reduced, and with AD pathology when levels are increased. They may represent novel markers of neurosecretory impairment in neurodegenerative disorders.