https://www.cell.com/cell/pdf/S0092-8674(19)31007-4.pdf

Alzheimer Disease: An Update on Pathobiology and Treatment Strategies.

With the potential development of new disease-modifying Alzheimer's disease (AD) therapies, simple, widely available screening tests are needed to identify which individuals, who are experiencing symptoms of cognitive or behavioral decline, should be further evaluated for initiation of treatment. A blood-based test for AD would be a less invasive and less expensive screening tool than the currently approved cerebrospinal fluid or amyloid β positron emission tomography (PET) diagnostic tests. We examined whether plasma tau phosphorylated at residue 181 (pTau181) could differentiate between clinically diagnosed or autopsy-confirmed AD and frontotemporal lobar degeneration. Plasma pTau181 concentrations were increased by 3.5-fold in AD compared to controls and differentiated AD from both clinically diagnosed (receiver operating characteristic area under the curve of 0.894) and autopsy-confirmed frontotemporal lobar degeneration (area under the curve of 0.878). Plasma pTau181 identified individuals who were amyloid β-PET-positive regardless of clinical diagnosis and correlated with cortical tau protein deposition measured by 18F-flortaucipir PET. Plasma pTau181 may be useful to screen for tau pathology associated with AD.

Diagnostic value of plasma phosphorylated tau181 in Alzheimer's disease and frontotemporal lobar degeneration.

For many years, blood-based biomarkers for Alzheimer's disease seemed unattainable, but recent results have shown that they could become a reality. Convincing data generated with new high-sensitivity assays have emerged with remarkable consistency across different cohorts, but also independent of the precise analytical method used. Concentrations in blood of amyloid and phosphorylated tau proteins associate with the corresponding concentrations in CSF and with amyloid-PET or tau-PET scans. Moreover, other blood-based biomarkers of neurodegeneration, such as neurofilament light chain and glial fibrillary acidic protein, appear to provide information on disease progression and potential for monitoring treatment effects. Now the question emerges of when and how we can bring these biomarkers to clinical practice. This step would pave the way for blood-based biomarkers to support the diagnosis of, and development of treatments for, Alzheimer's disease and other dementias. 

/pdf/blood-based-biomarkers-for-alzheimer-s-disease-towards-39eiy9b8.pdf

Blood-based biomarkers for Alzheimer's disease: towards clinical implementation

Multiple system atrophy (MSA) is a sporadic, adult-onset, relentlessly progressive neurodegenerative disorder, clinically characterized by various combinations of autonomic failure, parkinsonism and ataxia. The neuropathological hallmark of MSA are glial cytoplasmic inclusions consisting of misfolded α-synuclein. Selective atrophy and neuronal loss in striatonigral and olivopontocerebellar systems underlie the division into two main motor phenotypes of MSA-parkinsonian type and MSA-cerebellar type. Isolated autonomic failure and REM sleep behavior disorder are common premotor features of MSA. Beyond the core clinical symptoms, MSA manifests with a number of non-motor and motor features. Red flags highly specific for MSA may provide clues for a correct diagnosis, but in general the diagnostic accuracy of the second consensus criteria is suboptimal, particularly in early disease stages. In this chapter, the authors discuss the historical milestones, etiopathogenesis, neuropathological findings, clinical features, red flags, differential diagnosis, diagnostic criteria, imaging and other biomarkers, current treatment, unmet needs and future treatments for MSA.

Multiple system atrophy.

Clinical trial results presented in 2019 suggest that antibody-based removal of cerebral amyloid β (Aβ) plaques may possibly clear tau tangles and modestly slow cognitive decline in symptomatic Alzheimer's disease (AD). Although regulatory approval of this approach is still pending, preparing the healthcare system for the advent of disease-modifying therapies against AD is imperative. In particular, it will be necessary to identify the most suitable biomarkers to facilitate appropriate treatment of AD. Here, we give an update on recent developments in fluid and imaging biomarkers for AD-related pathologies and discuss potential approaches that could be adopted to screen for and clarify the underlying pathology in people seeking medical advice because of cognitive symptoms. We succinctly review recent data regarding biomarkers for Aβ and tau pathology, neurodegeneration, synaptic dysfunction, and inflammation, highlight the need for further research into common copathologies, and suggest how different biomarkers could be used (most likely in combination) to facilitate the development and clinical implementation of novel drug candidates against AD.

/pdf/biomarkers-for-alzheimer-s-disease-preparing-for-a-new-era-5a6pvmn4k6.pdf

Biomarkers for Alzheimer’s disease—preparing for a new era of disease-modifying therapies

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 10059 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.

/pdf/diagnostic-value-of-cerebrospinal-fluid-neurofilament-light-156e9buoja.pdf

Pijnenburg Yal

Papers

Diagnostic Value of Cerebrospinal Fluid Neurofilament Light Protein in Neurology: A Systematic Review and Meta-analysis