Background: Small vessel disease (SVD) represents a common often progressive condition in elderly people contributing to cognitive disability. The relationship between cerebrospinal fluid (CSF) ...biomarkers and imaging correlates of SVD was investigated, and the findings were hypothesized to be associated with a neuropsychological profile of SVD. Methods: CSF SVD-related biomarkers neurofilament light (NF-L), myelin basic protein (MBP), soluble amyloid precursor protein-β (sAPPβ), matrix metalloproteinases (MMPs), and tissue inhibitor of metalloproteinase (TIMP) were analysed in 46 non-demented elderly with imaging findings of SVD. We assessed the relationship between the CSF biomarkers and white matter hyperintensity (WMH) volume, diffusion-weighted imaging and atrophy as well as their association with neuropsychological profiles. Results: The WMH volume correlated with ventricular dilation, which was associated with executive function and speed and attention. Increased WMH and ventricular dilation were related to increased CSF levels of TIMP-1, NF-L and MBP and to decreased sAPPβ. A positive correlation was found between the CSF biomarker MMP-9 and WMH progression. Conclusions: The link between progressive WMH and MMP-9 suggests an involvement of the enzyme in white matter degeneration. CSF TIMP-1, NF-L, MBP and sAPPβ may function as biological markers of white matter damage.
Following the Russian occupation and annexation of Crimea, Western assessments of Russia's military capabilities rapidly changed from 'basket case' to 'menace'. In this pendulum swing, some estimates ...clearly overshot, especially concerning Russian anti-access/area-denial (A2/AD) capabilities. These were described as creating large no-go zones on NATO's eastern flank that could be overcome only at high risk or with new, exotic and costly kit. This impression could reinforce perceptions that the eastern allies could not be defended. This article argues that technical limitations, a wide range of possible countermeasures and experiences from air operations in Syria, Libya and Nagorno-Karabakh together suggest a less alarmist assessment of Russian A2/AD capabilities. But the threat should not be underestimated, and expanded NATO area-access assets are needed, as Russia will continuously improve its capabilities and the status quo is fluid.
IMPORTANCE: Neurofilament light protein (NfL) is elevated in cerebrospinal fluid (CSF) of a number of neurological conditions compared with healthy controls (HC) and is a candidate biomarker for ...neuroaxonal damage. The influence of age and sex is largely unknown, and levels across neurological disorders have not been compared systematically to date. OBJECTIVES: To assess the associations of age, sex, and diagnosis with NfL in CSF (cNfL) and to evaluate its potential in discriminating clinically similar conditions. DATA SOURCES: PubMed was searched for studies published between January 1, 2006, and January 1, 2016, reporting cNfL levels (using the search terms neurofilament light and cerebrospinal fluid) in neurological or psychiatric conditions and/or in HC. STUDY SELECTION: Studies reporting NfL levels measured in lumbar CSF using a commercially available immunoassay, as well as age and sex. DATA EXTRACTION AND SYNTHESIS: Individual-level data were requested from study authors. Generalized linear mixed-effects models were used to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels, with cohort of origin modeled as a random intercept. MAIN OUTCOME AND MEASURE: The cNfL levels adjusted for age and sex across diagnoses. RESULTS: Data were collected for 10 059 individuals (mean SD age, 59.7 18.8 years; 54.1% female). Thirty-five diagnoses were identified, including inflammatory diseases of the central nervous system (n = 2795), dementias and predementia stages (n = 4284), parkinsonian disorders (n = 984), and HC (n = 1332). The cNfL was elevated compared with HC in a majority of neurological conditions studied. Highest levels were observed in cognitively impaired HIV-positive individuals (iHIV), amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and Huntington disease. In 33.3% of diagnoses, including HC, multiple sclerosis, Alzheimer disease (AD), and Parkinson disease (PD), cNfL was higher in men than women. The cNfL increased with age in HC and a majority of neurological conditions, although the association was strongest in HC. The cNfL overlapped in most clinically similar diagnoses except for FTD and iHIV, which segregated from other dementias, and PD, which segregated from atypical parkinsonian syndromes. CONCLUSIONS AND RELEVANCE: These data support the use of cNfL as a biomarker of neuroaxonal damage and indicate that age-specific and sex-specific (and in some cases disease-specific) reference values may be needed. The cNfL has potential to assist the differentiation of FTD from AD and PD from atypical parkinsonian syndromes.
CONTEXT Small single-center studies have shown that cerebrospinal fluid (CSF) biomarkers may be useful to identify incipient Alzheimer disease (AD) in patients with mild cognitive impairment (MCI), ...but large-scale multicenter studies have not been conducted. OBJECTIVE To determine the diagnostic accuracy of CSF β-amyloid1-42 (Aβ42), total tau protein (T-tau), and tau phosphorylated at position threonine 181 (P-tau) for predicting incipient AD in patients with MCI. DESIGN, SETTING, AND PARTICIPANTS The study had 2 parts: a cross-sectional study involving patients with AD and controls to identify cut points, followed by a prospective cohort study involving patients with MCI, conducted 1990-2007. A total of 750 individuals with MCI, 529 with AD, and 304 controls were recruited by 12 centers in Europe and the United States. Individuals with MCI were followed up for at least 2 years or until symptoms had progressed to clinical dementia. MAIN OUTCOME MEASURES Sensitivity, specificity, positive and negative likelihood ratios (LRs) of CSF Aβ42, T-tau, and P-tau for identifying incipient AD. RESULTS During follow-up, 271 participants with MCI were diagnosed with AD and 59 with other dementias. The Aβ42 assay in particular had considerable intersite variability. Patients who developed AD had lower median Aβ42 (356; range, 96-1075 ng/L) and higher P-tau (81; range, 15-183 ng/L) and T-tau (582; range, 83-2174 ng/L) levels than MCI patients who did not develop AD during follow-up (579; range, 121-1420 ng/L for Aβ42; 53; range, 15-163 ng/L for P-tau; and 294; range, 31-2483 ng/L for T-tau, P < .001). The area under the receiver operating characteristic curve was 0.78 (95% confidence interval CI, 0.75-0.82) for Aβ42, 0.76 (95% CI, 0.72-0.80) for P-tau, and 0.79 (95% CI, 0.76-0.83) for T-tau. Cut-offs with sensitivity set to 85% were defined in the AD and control groups and tested in the MCI group, where the combination of Aβ42/P-tau ratio and T-tau identified incipient AD with a sensitivity of 83% (95% CI, 78%-88%), specificity 72% (95% CI, 68%-76%), positive LR, 3.0 (95% CI, 2.5-3.4), and negative LR, 0.24 (95% CI, 0.21-0.28). The positive predictive value was 62% and the negative predictive value was 88%. CONCLUSIONS This multicenter study found that CSF Aβ42, T-tau, and P-tau identify incipient AD with good accuracy, but less accurately than reported from single-center studies. Intersite assay variability highlights a need for standardization of analytical techniques and clinical procedures.
Core CSF changes in Alzheimer disease (AD) are decreased amyloid β(1-42), increased total tau, and increased phospho-tau, probably indicating amyloid plaque accumulation, axonal degeneration, and ...tangle pathology, respectively. These biomarkers identify AD already at the predementia stage, but their diagnostic performance might be affected by age-dependent increase of AD-type brain pathology in cognitively unaffected elderly.
We investigated effects of age on the diagnostic performance of CSF biomarkers in a uniquely large multicenter study population, including a cross-sectional cohort of 529 patients with AD dementia (median age 71, range 43-89 years) and 304 controls (67, 44-91 years), and a longitudinal cohort of 750 subjects without dementia with mild cognitive impairment (69, 43-89 years) followed for at least 2 years, or until dementia diagnosis.
The specificities for subjects without AD and the areas under the receiver operating characteristics curves decreased with age. However, the positive predictive value for a combination of biomarkers remained stable, while the negative predictive value decreased only slightly in old subjects, as an effect of the high AD prevalence in older ages.
Although the diagnostic accuracies for AD decreased with age, the predictive values for a combination of biomarkers remained essentially stable. The findings highlight biomarker variability across ages, but support the use of CSF biomarkers for AD even in older populations.
Neurofibrillary tangles composed of aggregated tau protein are one of the neuropathological hallmarks of Alzheimer disease (AD) and correlate with clinical disease severity. Monoclonal antibodies ...targeting tau may have the potential to ameliorate AD progression by slowing or stopping the spread and/or accumulation of pathological tau.
To evaluate the safety and efficacy of the monoclonal anti-tau antibody semorinemab in prodromal to mild AD.
This phase 2 randomized, double-blind, placebo-controlled, parallel-group clinical trial was conducted between October 18, 2017, and July 16, 2020, at 97 sites in North America, Europe, and Australia. Individuals aged 50 to 80 years (inclusive) with prodromal to mild AD, Mini-Mental State Examination scores between 20 and 30 (inclusive), and confirmed β-amyloid pathology (by positron emission tomography or cerebrospinal fluid) were included.
During the 73-week blinded study period, participants received intravenous infusions of placebo or semorinemab (1500 mg, 4500 mg, or 8100 mg) every 2 weeks for the first 3 infusions and every 4 weeks thereafter.
The primary outcomes were change from baseline on the Clinical Dementia Rating-Sum of Boxes score from baseline to week 73 and assessments of the safety and tolerability for semorinemab compared with placebo.
In the modified intent-to-treat cohort (n = 422; mean SD age, 69.6 7.0 years; 235 women 55.7%), similar increases were seen on the Clinical Dementia Rating-Sum of Boxes score in the placebo (n = 126; Δ = 2.19 95% CI, 1.74-2.63) and semorinemab (1500 mg: n = 86; Δ = 2.36 95% CI, 1.83-2.89; 4500 mg: n = 126; Δ = 2.36 95% CI, 1.92-2.79; 8100 mg: n = 84; Δ = 2.41 95% CI, 1.88-2.94) arms. In the safety-evaluable cohort (n = 441), similar proportions of participants experienced adverse events in the placebo (130 93.1%) and semorinemab (1500 mg: 89 88.8%; 4500 mg: 132 94.7%; 8100 mg: 90 92.2%) arms.
In participants with prodromal to mild AD in this randomized clinical trial, semorinemab did not slow clinical AD progression compared with placebo throughout the 73-week study period but did demonstrate an acceptable and well-tolerated safety profile. Additional studies of anti-tau antibodies may be needed to determine the clinical utility of this therapeutic approach.
ClinicalTrials.gov Identifier: NCT03289143.
Abstract Introduction Cerebrospinal fluid collection by lumbar puncture (LP) is performed in the diagnostic workup of several neurological brain diseases. Reluctance to perform the procedure is among ...others due to a lack of standards and guidelines to minimize the risk of complications, such as post-LP headache or back pain. Methods We provide consensus guidelines for the LP procedure to minimize the risk of complications. The recommendations are based on (1) data from a large multicenter LP feasibility study (evidence level II-2), (2) systematic literature review on LP needle characteristics and post-LP complications (evidence level II-2), (3) discussion of best practice within the Joint Programme Neurodegenerative Disease Research Biomarkers for Alzheimer's disease and Parkinson's Disease and Biomarkers for Multiple Sclerosis consortia (evidence level III). Results Our consensus guidelines address contraindications, as well as patient-related and procedure-related risk factors that can influence the development of post-LP complications. Discussion When an LP is performed correctly, the procedure is well tolerated and accepted with a low complication rate.
Vascular cognitive impairment (VCI) is a heterogeneous entity with multiple aetiologies, all linked to underlying vascular disease. Among these, VCI related to subcortical small vessel disease (SSVD) ...is emerging as a major homogeneous subtype. Its progressive course raises the need for biomarker identification and/or development for adequate therapeutic interventions to be tested. In order to shed light in the current status on biochemical markers for VCI-SSVD, experts in field reviewed the recent evidence and literature data.
The group conducted a comprehensive search on Medline, PubMed and Embase databases for studies published until 15.01.2017. The proposal on current status of biochemical markers in VCI-SSVD was reviewed by all co-authors and the draft was repeatedly circulated and discussed before it was finalized.
This review identifies a large number of biochemical markers derived from CSF and blood. There is a considerable overlap of VCI-SSVD clinical symptoms with those of Alzheimer's disease (AD). Although most of the published studies are small and their findings remain to be replicated in larger cohorts, several biomarkers have shown promise in separating VCI-SSVD from AD. These promising biomarkers are closely linked to underlying SSVD pathophysiology, namely disruption of blood-CSF and blood-brain barriers (BCB-BBB) and breakdown of white matter myelinated fibres and extracellular matrix, as well as blood and brain inflammation. The leading biomarker candidates are: elevated CSF/blood albumin ratio, which reflects BCB/BBB disruption; altered CSF matrix metalloproteinases, reflecting extracellular matrix breakdown; CSF neurofilment as a marker of axonal damage, and possibly blood inflammatory cytokines and adhesion molecules. The suggested SSVD biomarker deviations contrasts the characteristic CSF profile in AD, i.e. depletion of amyloid beta peptide and increased phosphorylated and total tau.
Combining SSVD and AD biomarkers may provide a powerful tool to identify with greater precision appropriate patients for clinical trials of more homogeneous dementia populations. Thereby, biomarkers might promote therapeutic progress not only in VCI-SSVD, but also in AD.
Several insurgent groups have financed their arms procurement through drug trafficking, explaining in part the long duration of conflicts in drug producing countries. Incomes generated from this ...trade do
not
however automatically translate into improved military capabilities, since access to military-grade weapons typically requires tacit or active state support. Hence, two groups with similar types of funding can still have access to very different types of armaments, impacting their operational capability. This paper compares the arms procurement of the Fuerzas Armadas Revolucionarias de Colombia (FARC) and the United Wa State Army (UWSA) in Myanmar. Both insurgent groups have procured arms through networks and with finances from the drug trade. The UWSA's 20,000-strong force and significant armaments, including Man-portable air defense systems (MANPADS) believed to be provided by China, is largely supported by these illicit activities and the networks they provide. FARC has ample access to small arms, the acquisition of which has been financed by taxation of the drug trade. In spite of significant incomes, FARC however until very recently lacked access to MANPADS, a fact which has significantly hampered its ability to withstand the Colombian counterinsurgency campaign, specifically targeted aerial assaults. The exploratory comparisons drawn in this paper offer insights into how insurgent groups can pass a crucial threshold of arms procurement, funded by illicit activities, that renders their dissolution far more difficult, while also highlighting the continued importance of state support in explaining rebel group resilience.
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