Risk of stroke with different levels of leisure-time physical activity: a systematic review and meta-analysis of prospective cohort studies.

BACKGROUND: Leisure-time physical activity (LTPA) protects against vascular diseases. Whether and to what extent different levels of LTPA, including lower ones, benefit stroke prevention is still unclear. METHODS: We searched prospective cohort studies, indexed on PubMed and Scopus, published in English up to 22 April 2023, that investigated, in a general healthy population, the relationship between different predefined LTPA levels, compared with inactivity, and the risk of any type of stroke. We applied random effect modelling for meta-analyses and meta-regression to control for the impact of age and sex. RESULTS: Out of 3064 screened articles, 15 articles on 16 cohorts of subjects were included in meta-analyses, with a total of 752 050 followed-up subjects. Mean follow-up was 125.7±77.5 months. Included studies identified three (none, below target and ideal) to five (none, insufficient, low, moderate and intense) levels of LTPA. In the five studies identifying three levels of LTPA, compared with no LTPA, below target (risk ratio (RR)=0.82, 95% CI=0.75 to 0.88) and ideal LTPA significantly reduced stroke risk (RR=0.71, 95% CI=0.58 to 0.86).Lower levels of LTPA also mitigated stroke risk in studies reporting on four (n=6; RR=0.73, 95% CI=0.62 to 0.87 favouring moderate LTPA over no LTPA) and five levels (n=2; RR=0.71, 95% CI=0.58 to 0.88 favouring moderate LTPA over no LTPA). The benefits of LTPA were independent of age and sex. CONCLUSIONS: According to our results, all levels of LTPA can be beneficial for stroke prevention, including levels currently regarded as low or insufficient. People should be encouraged to be physically active even at the lowest levels. PROSPERO REGISTRATION NUMBER: CRD42023425302.

Incremental value of serum neurofilament light chain and glial fibrillary acidic protein as blood-based biomarkers for predicting functional outcome in severe acute ischemic stroke.

INTRODUCTION: Blood-based biomarkers may improve prediction of functional outcome in patients with acute ischemic stroke. The role of neurofilament light chain (NfL) and glial fibrillary acidic (GFAP) as potential biomarkers especially in severe stroke patients is unknown. PATIENTS AND METHODS: Prospective, monocenter, cohort study including consecutive patients with severe ischemic stroke in the anterior circulation on admission (NIHSS score ⩾ 6 points or indication for mechanical thrombectomy). Outcome was assessed 3 months after the index stroke by the modified Rankin Scale (mRS). Serum biomarkers levels of NfL and GFAP were determined by ultrasensitive ELISA. Univariate and multivariate logistic regression models were performed to determine the association of biomarker levels and functional disability. Discrimination, calibration, and overall performance were analyzed in different models via AUROC, calibration plots (with Emax and Eavg), Brier-score and R2 using variables, identified as important covariates for functional outcome in previous studies. RESULTS: Between 06/2020 and 08/2021, 213 patients were included [47% female, mean age 76 (SD ± 12) years, median NIHSS score 13 (interquartile range, IQR 9; 17)]. Biomarker serum levels were measured at a median of 1 [IQR, 1; 2] day after admission. Compared to patients with mRS 0-2 at 3 months, patients with mRS 3-6 had higher serum levels of NfL (median: 136 pg/ml vs 41 pg/ml; p < 0.0001) and GFAP (700 ng/ml vs 9.6 ng/ml; p < 0.0001). Both biomarkers were significantly associated with functional outcome [adjusted logistic regression, odds ratio (95% CI) for NfL: 2.63 (1.62; 4.56), GFAP: 2.16 (1.58; 3.09)]. In all models the addition of serum NfL led to a significant improvement in the AUROC, as did the addition of serum GFAP. Calibration plots showed high agreement between the predicted and observed outcomes and after addition of the two blood-based biomarkers there was an improvement of the overall performance. CONCLUSION: Prediction of functional outcome after severe acute ischemic stroke was improved by the blood-based biomarkers serum NfL and GFAP, measured in the acute phase of stroke. These findings have to be replicated in independent external cohorts.Study registration: DRKS00022064.

Safety and outcomes of different endovascular treatment techniques for anterior circulation ischaemic stroke in the elderly: data from the Imperial College Thrombectomy Registry.

BACKGROUND: Although previous studies investigated the main predictors of outcomes after endovascular thrombectomy (EVT) in patients aged 80 years and older, less is known about the impact of the procedural features on outcomes in elderly patients. The aim of this study was to investigate the influence of EVT technical procedures on the main 3-month outcomes in a population of patients aged 80 years and older. METHODS: This observational, prospective, single-centre study included consecutive patients with acute LVO ischaemic stroke of the anterior circulation. The study outcomes were functional independence at 3 months after EVT (defined as a mRS score of 0-2), successful reperfusion (mTICI ≥ 2b), incidence of haeamorrhagic transformation, and 90-day all cause of mortality. RESULTS: Our cohort included 497 patients with acute ischaemic stroke due to LVO treated with EVT. Among them, 105 (21.1%) patients were aged ≥ 80 years. In the elderly group, multivariable regression analysis showed that thromboaspiration technique vs stent-retriever was the single independent predictor of favourable post-procedural TICI score (OR = 7.65, 95%CI = 2.22-26.32, p = 0.001). CONCLUSIONS: Our study suggests that EVT for LVO stroke in the elderly could be safe. The use of thromboaspiration was associated with positive reperfusion outcome in this population. Further studies in larger series are warranted to confirm the present results and to evaluate the safety and efficacy of EVT in the elderly and oldest adults.

Cerebrospinal fluid NPTX2 changes and relationship with regional brain metabolism metrics across mild cognitive impairment due to Alzheimer's disease.

BACKGROUND: Neuronal pentraxin-2 (NPTX2), crucial for synaptic functioning, declines in cerebrospinal fluid (CSF) as cognition deteriorates. The variations of CSF NPTX2 across mild cognitive impairment (MCI) due to Alzheimer's disease (AD) and its association with brain metabolism remain elusive, albeit relevant for patient stratification and pathophysiological insights. METHODS: We retrospectively analyzed 49 MCI-AD patients grouped by time until dementia (EMCI, n = 34 progressing within 2 years; LMCI, n = 15 progressing later/stable at follow-up). We analyzed demographic variables, cognitive status (MMSE score), and CSF NPTX2 levels using a commercial ELISA assay in EMCI, LMCI, and a control group of age-/sex-matched individuals with other non-dementing disorders (OND). Using [18F]FDG PET scans for voxel-based analysis, we explored correlations between regional brain metabolism metrics and CSF NPTX2 levels in MCI-AD patients, accounting for age. RESULTS: Baseline and follow-up MMSE scores were lower in LMCI than EMCI (p value = 0.006 and p < 0.001). EMCI exhibited significantly higher CSF NPTX2 values than both LMCI (p = 0.028) and OND (p = 0.006). We found a significant positive correlation between NPTX2 values and metabolism of bilateral precuneus in MCI-AD patients (p < 0.005 at voxel level, p < 0.05 with family-wise error correction at the cluster level). CONCLUSIONS: Higher CSF NPTX2 in EMCI compared to controls and LMCI suggests compensatory synaptic responses to initial AD pathology. Disease progression sees these mechanisms overwhelmed, lowering CSF NPTX2 approaching dementia. Positive CSF NPTX2 correlation with precuneus glucose metabolism links to AD-related metabolic changes across MCI course. These findings posit CSF NPTX2 as a promising biomarker for both AD staging and progression risk stratification.

Serum ß-synuclein, neurofilament light chain and glial fibrillary acidic protein as prognostic biomarkers in moderate-to-severe acute ischemic stroke.

We aimed to assess the prognostic value of serum ß-synuclein (ß-syn), neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in patients with moderate-to-severe acute ischemic stroke. We measured ß-syn, GFAP and NfL in serum samples collected one day after admission in 30 adult patients with moderate-to-severe ischemic stroke due to middle cerebral artery (MCA) occlusion. We tested the associations between biomarker levels and clinical and radiological scores (National Institute of Health Stroke Scale scores, NIHSS, and Alberta Stroke Program Early CT Score, ASPECTS), as well as measures of functional outcome (modified Rankin Scale, mRS). Serum biomarkers were significantly associated with ASPECTS values (ß-syn p = 0.0011, GFAP p = 0.0002) but not with NIHSS scores at admission. Patients who received mechanical thrombectomy and intravenous thrombolysis showed lower ß-syn (p = 0.029) und NfL concentrations (p = 0.0024) compared to patients who received only mechanical thrombectomy. According to median biomarker levels, patients with high ß-syn, NfL or GFAP levels showed, after therapy, lower clinical improvement (i.e., lower 24-h NIHSS change), higher NIHSS scores during hospitalization and higher mRS scores at 3-month follow-up. Elevated serum concentrations of ß-syn (p = 0.016), NfL (p = 0.020) or GFAP (p = 0.010) were significantly associated with 3-month mRS of 3-6 vs. 0-2 even after accounting for age, sex and renal function. In patients with moderate-to-severe acute ischemic stroke, serum ß-syn, NfL and GFAP levels associated with clinical and radiological scores at different timepoints and were able to predict short- and middle-term clinical outcomes.

The Underestimated Relevance of Alzheimer's Disease Copathology in Amyotrophic Lateral Sclerosis.

Concomitant Alzheimer's disease (AD) pathology can be observed in approximately 10-15% of cases with amyotrophic lateral sclerosis (ALS). ALS-AD patients have a higher prevalence of amnestic cognitive disturbances, which may often precede motor symptoms. Cerebrospinal fluid (CSF) AD core biomarkers usually show no or slightly significant changes in ALS, whereas blood phosphorylated tau protein might be increased independently from AD copathology. Neurofilament proteins are consistently elevated in CSF and blood of ALS, but have been poorly investigated in ALS-AD. All these issues should be taken into account when using fluid biomarkers as inclusion criteria or secondary endpoints in clinical trials.

Plasma ß-synuclein, GFAP, and neurofilaments in patients with malignant gliomas undergoing surgical and adjuvant therapy.

We analyzed the longitudinal concentrations and prognostic roles of plasma ß-synuclein (ß-syn), glial fibrillary acidic protein (GFAP), and neurofilament proteins (NfL and NfH) in 33 patients with malignant gliomas, who underwent surgical and adjuvant therapy. GFAP and NfL levels were increased in patients with glioblastoma compared to cases with other tumors. ß-syn, NfL and NfH increased after surgery, whereas GFAP decreased at long-term follow-up. ß-syn and neurofilament concentrations were influenced by surgery and/or radiotherapy regimens. GFAP and neurofilament levels were significantly associated with survival. Plasma neuronal and astrocytic biomarkers are differentially altered in malignant glioma types and displayed distinct trajectories after surgical and adjuvant therapy.

High diagnostic performance of plasma and cerebrospinal fluid beta-synuclein for sporadic Creutzfeldt-Jakob disease.

Beta-synuclein is a promising cerebrospinal fluid and blood biomarker of synaptic damage. Here we analysed its accuracy in the discrimination between sporadic Creutzfeldt-Jakob disease (n = 150) and non-prion rapidly progressive dementias (n = 106). In cerebrospinal fluid, beta-synuclein performed better than protein 14-3-3 (AUC 0.95 vs. 0.89) and, to a lesser extent, than total tau (AUC 0.92). Further, the diagnostic value of plasma beta-synuclein (AUC 0.91) outperformed that of plasma tau (AUC 0.79) and neurofilament light chain protein (AUC 0.65) and was comparable to that of cerebrospinal fluid biomarkers. Beta-synuclein might represent the first highly accurate blood biomarker for the diagnosis of sporadic Creutzfeldt-Jakob disease.

CSF Synaptic Biomarkers in AT(N)-Based Subgroups of Lewy Body Disease.

BACKGROUND AND OBJECTIVES: Patients with Lewy body disease (LBD) often show a co-occurring Alzheimer disease (AD) pathology. CSF biomarkers allow the detection in vivo of AD-related pathologic hallmarks included in the amyloid-tau-neurodegeneration (AT(N)) classification system. Here, we aimed to investigate whether CSF biomarkers of synaptic and neuroaxonal damage are correlated with the presence of AD copathology in LBD and can be useful to differentiate patients with LBD with different AT(N) profiles. METHODS: We retrospectively measured CSF levels of AD core biomarkers (Aß42/40 ratio, phosphorylated tau protein, and total tau protein) and of synaptic (ß-synuclein, α-synuclein, synaptosomal-associated protein 25 [SNAP-25], and neurogranin) and neuroaxonal proteins (neurofilament light chain [NfL]) in 28 cognitively unimpaired participants with nondegenerative neurologic conditions and 161 participants with a diagnosis of either LBD or AD (at both mild cognitive impairment, AD-MCI, and dementia stages, AD-dem). We compared CSF biomarker levels in clinical and AT(N)-based subgroups. RESULTS: CSF ß-synuclein, α-synuclein, SNAP-25, neurogranin, and NfL levels did not differ between LBD (n = 101, age 67.2 ± 7.8 years, 27.7% females) and controls (age 64.8 ± 8.6 years, 39.3% females) and were increased in AD (AD-MCI: n = 30, AD-dem: n = 30, age 72.3 ± 6.0 years, 63.3% females) compared with both groups (p < 0.001 for all comparisons). In LBD, we found increased levels of synaptic and neuroaxonal degeneration biomarkers in patients with A+T+ (LBD/A+T+) than with A-T- profiles (LBD/A-T-) (p < 0.01 for all), and ß-synuclein showed the highest discriminative accuracy between the 2 groups (area under the curve 0.938, 95% CI 0.884-0.991). CSF ß-synuclein (p = 0.0021), α-synuclein (p = 0.0099), and SNAP-25 concentrations (p = 0.013) were also higher in LBD/A+T+ than in LBD/A+T- cases, which had synaptic biomarker levels within the normal range. CSF α-synuclein was significantly decreased only in patients with LBD with T- profiles compared with controls (p = 0.0448). Moreover, LBD/A+T+ and AD cases did not differ in any biomarker level. DISCUSSION: LBD/A+T+ and AD cases showed significantly increased CSF levels of synaptic and neuroaxonal biomarkers compared with LBD/A-T- and control subjects. Patients with LBD and AT(N)-based AD copathology showed, thus, a distinct signature of synaptic dysfunction from other LBD cases. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that CSF levels of ß-synuclein, α-synuclein, SNAP-25, neurogranin, and NfL are higher in patients with AD than in patients with LBD.

Prognostic performance of blood neurofilament light chain protein in hospitalized COVID-19 patients without major central nervous system manifestations: an individual participant data meta-analysis.

BACKGROUND AND AIMS: To investigate the prognostic value of blood neurofilament light chain protein (NfL) levels in the acute phase of coronavirus disease 2019 (COVID-19). METHODS: We conducted an individual participant data (IPD) meta-analysis after screening on MEDLINE and Scopus to May 23rd 2022. We included studies with hospitalized adult COVID-19 patients without major COVID-19-associated central nervous system (CNS) manifestations and with a measurement of blood NfL in the acute phase as well as data regarding at least one clinical outcome including intensive care unit (ICU) admission, need of mechanical ventilation (MV) and death. We derived the age-adjusted measures NfL Z scores and conducted mixed-effects modelling to test associations between NfL Z scores and other variables, encompassing clinical outcomes. Summary receiver operating characteristic curves (SROCs) were used to calculate the area under the curve (AUC) for blood NfL. RESULTS: We identified 382 records, of which 7 studies were included with a total of 669 hospitalized COVID-19 cases (mean age 66.2 ± 15.0 years, 68.1% males). Median NfL Z score at admission was elevated compared to the age-corrected reference population (2.37, IQR: 1.13-3.06, referring to 99th percentile in healthy controls). NfL Z scores were significantly associated with disease duration and severity. Higher NfL Z scores were associated with a higher likelihood of ICU admission, need of MV, and death. SROCs revealed AUCs of 0.74, 0.80 and 0.71 for mortality, need of MV and ICU admission, respectively. CONCLUSIONS: Blood NfL levels were elevated in the acute phase of COVID-19 patients without major CNS manifestations and associated with clinical severity and poor outcome. The marker might ameliorate the performance of prognostic multivariable algorithms in COVID-19.

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.

Exploring the brain metabolic correlates of process-specific CSF biomarkers in patients with MCI due to Alzheimer's disease: preliminary data.

We explored the brain metabolism correlates of emergent cerebrospinal fluid (CSF) biomarkers in a group of 26 patients with prodromal Alzheimer's disease (AD). Distinct volumes of interest (VOIs) expressed the sites of correlation between CSF biomarkers and brain metabolism as determined on [18F]FDG-PET images, as well as of significant hypometabolism in patients compared to healthy controls. Neurogranin- and α-synuclein-VOIs included left precuneus and/or posterior cingulate cortex (PC and/or PCC) and partially overlapped hypometabolism at those sites. ß-synuclein- and neurofilament light chain (NfL)-VOIs regarded either left or right lateral temporal areas, respectively, with partial overlap with hypometabolism only for the ß-synuclein-VOI, whereas the NfL-VOI did not include hypometabolic regions. We speculate that CSF neurogranin and α-synuclein express an already established hippocampal damage leading to PC and/or PCC deafferentation and hypometabolism. ß-synuclein may represent the progression of synaptopathy in the temporal lobe, while NfL the axonal injury in right temporal regions where neuronal loss is not yet evident.

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 levels of proenkephalin and prodynorphin are differentially altered in Huntington's and Parkinson's disease.

BACKGROUND: Proenkephalin (PENK) and prodynorphin (PDYN) are peptides mainly produced by the striatal medium spiny projection neurons (MSNs) under dopaminergic signaling. Therefore, they may represent candidate biomarkers in Huntington's disease (HD) and Parkinson's disease (PD), two neurodegenerative diseases characterized by striatal atrophy and/or dysfunction. METHODS: Using an in-house established liquid chromatography-tandem mass spectrometry (LC-MS/MS) method in multiple reaction monitoring mode (MRM) we measured cerebrospinal fluid (CSF) levels of PENK- and PDYN- derived peptides in patients with HD (n = 47), PD (n = 61), Alzheimer's disease (n = 11), amyotrophic lateral sclerosis (n = 14) and in 92 control subjects. Moreover, we investigated the possible associations between biomarkers and disease severity scales in HD and PD and the effect of dopaminergic therapy on biomarker levels in PD. RESULTS: In HD, CSF PENK- and PDYN-derived peptide levels were significantly decreased compared to all other groups and were associated with disease severity scores. In PD, both biomarkers were within the normal range, but higher PDYN levels were found in dopamine-treated compared to untreated patients. In PD, both CSF PENK and PDYN did not correlate with clinical severity scales. CONCLUSIONS: CSF PENK- and PDYN-derived peptides appeared to be promising pathogenetic and disease severity markers in HD, reflecting the ongoing striatal neurodegeneration along with the loss of MSNs. In PD patients, CSF PDYN showed a limitative role as a possible pharmacodynamic marker during dopaminergic therapy, but further investigations are needed.

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.