•Neurofilament levels are elevated in most neurodegenerative conditions.•Levels predict cross-sectional and longitudinal cognitive and clinical outcomes.•There is minimal work relating neurofilaments ...to in vivo white matter damage.•It is unclear how neurofilament light and heavy chains relate to one another.•Neurofilaments are promising biomarkers, but more work needs to be done.
Neurofilaments are proteins selectively expressed in the cytoskeleton of neurons, and increased levels are a marker of damage. Elevated neurofilament levels can serve as a marker of ongoing disease activity as well as a tool to measure response to therapeutic intervention. The potential utility of neurofilaments has drastically increased as recent advances have made it possible to measure levels in both the cerebrospinal fluid and blood. There is mounting evidence that neurofilament light chain (NfL) and phosphorylated neurofilament heavy chain (NfH) are abnormal in a host of neurodegenerative diseases. In this review we examine how both of these proteins behave across diseases and what we know about how these biomarkers relate to in vivo white matter pathology and each other.
To examine the independent and interactive influences of neuroimaging biomarkers on retrospective cognitive decline.
A total of 152 middle-aged and older adult participants with at least 2 clinical ...and cognitive assessments, a Clinical Dementia Rating score of 0 or 0.5, and a flortaucipir (
F-AV-1451) tau PET scan, a florbetapir (
F-AV-45) amyloid PET scan, and a structural MRI scan were recruited from the Knight Alzheimer Disease Research Center at Washington University in St. Louis. Cognition was assessed with standard measures reflecting episodic memory, executive functioning, semantic fluency, and processing speed.
Results from retrospective longitudinal analyses showed that each biomarker had a univariate association with the global cognitive composite; however, when each marker was analyzed in a single statistical model, only tau was a significant predictor of global cognitive decline. There was an interaction between tau and amyloid such that tau-related cognitive decline was worse in individuals with high amyloid. There was also an interaction with hippocampal volume indicating that individuals with high levels of all 3 pathologies exhibited the greatest declines in cognition. Additional analyses within each cognitive domain indicated that tau had the largest negative influence on tests of episodic memory and executive functioning.
Together, these results suggest that increasing levels of tau most consistently relate to declines in cognition preceding biomarker collection. These findings support models of Alzheimer disease (AD) staging that suggest that elevated β-amyloid alone may be insufficient to produce cognitive change in individuals at risk for AD and support the use of multiple biomarkers to stage AD progression.
Racial differences in molecular biomarkers for Alzheimer disease may suggest race-dependent biological mechanisms.
To ascertain whether there are racial disparities in molecular biomarkers for ...Alzheimer disease.
A total of 1255 participants (173 African Americans) were enrolled from January 1, 2004, through December 31, 2015, in longitudinal studies at the Knight Alzheimer Disease Research Center at Washington University and completed a magnetic resonance imaging study of the brain and/or positron emission tomography of the brain with Pittsburgh compound B (radioligand for aggregated amyloid-β) and/or cerebrospinal fluid (CSF) assays for the concentrations of amyloid-β42, total tau, and phosphorylated tau181. Independent cross-sectional analyses were conducted from April 22, 2016, to August 27, 2018, for each biomarker modality with an analysis of variance or analysis of covariance including age, sex, educational level, race, apolipoprotein E (APOE) ε4 allele status, and clinical status (normal cognition or dementia). All biomarker assessments were conducted without knowledge of the clinical status of the participants.
The primary outcomes were hippocampal volumes adjusted for differences in intracranial volumes, global cerebral amyloid burden as transformed into standardized uptake value ratios (partial volume corrected), and CSF concentrations of amyloid-β42, total tau, and phosphorylated tau181.
Of the 1255 participants (707 women and 548 men; mean SD age, 70.8 9.9 years), 116 of 173 African American participants (67.1%) and 724 of 1082 non-Hispanic white participants (66.9%) had normal cognition. There were no racial differences in the frequency of cerebral ischemic lesions noted on results of brain magnetic resonance imaging, mean cortical standardized uptake value ratios for Pittsburgh compound B, or for amyloid-β42 concentrations in CSF. However, in individuals with a reported family history of dementia, mean (SE) total hippocampal volumes were lower for African American participants than for white participants (6418.26 138.97 vs 6990.50 44.10 mm3). Mean (SE) CSF concentrations of total tau were lower in African American participants than in white participants (293.65 34.61 vs 443.28 18.20 pg/mL; P < .001), as were mean (SE) concentrations of phosphorylated tau181 (53.18 4.91 vs 70.73 2.46 pg/mL; P < .001). There was a significant race by APOE ε4 interaction for both CSF total tau and phosphorylated tau181 such that only APOE ε4-positive participants showed the racial differences.
The results of this study suggest that analyses of molecular biomarkers of Alzheimer disease should adjust for race. The lower CSF concentrations of total tau and phosphorylated tau181 in African American individuals appear to reflect a significant race by APOE ε4 interaction, suggesting a differential effect of this Alzheimer risk variant in African American individuals compared with white individuals.
Astrocytes are proposed to participate in brain energy metabolism by supplying substrates to neurons from their glycogen stores and from glycolysis. However, the molecules involved in metabolic ...sensing and the molecular pathways responsible for metabolic coupling between different cell types in the brain are not fully understood. Here we show that a recently cloned bicarbonate (HCO3−) sensor, soluble adenylyl cyclase (sAC), is highly expressed in astrocytes and becomes activated in response to HCO3− entry via the electrogenic NaHCO3 cotransporter (NBC). Activated sAC increases intracellular cAMP levels, causing glycogen breakdown, enhanced glycolysis, and the release of lactate into the extracellular space, which is subsequently taken up by neurons for use as an energy substrate. This process is recruited over a broad physiological range of K+ext and also during aglycemic episodes, helping to maintain synaptic function. These data reveal a molecular pathway in astrocytes that is responsible for brain metabolic coupling to neurons.
► Astrocytes express bicarbonate-sensitive soluble adenylyl cyclase (sAC) ► Depolarization and bicarbonate entry increase cAMP in astrocytes ► sAC triggers glycogen breakdown and lactate efflux from astrocytes ► sAC protects synaptic function by lactate efflux from astrocytes
Choi et al. show that astrocytes express bicarbonate-sensitive soluble adenylyl cyclase that acts as a metabolic sensor of neuronal activity and supplies lactate derived from glycogen breakdown in astrocytes to maintain neuronal activity when alternative energy sources are needed.
High-throughput mRNA sequencing (RNA-Seq) promises simultaneous transcript discovery and abundance estimation. However, this would require algorithms that are not restricted by prior gene annotations ...and that account for alternative transcription and splicing. Here we introduce such algorithms in an open-source software program called Cufflinks. To test Cufflinks, we sequenced and analyzed >430 million paired 75-bp RNA-Seq reads from a mouse myoblast cell line over a differentiation time series. We detected 13,692 known transcripts and 3,724 previously unannotated ones, 62% of which are supported by independent expression data or by homologous genes in other species. Over the time series, 330 genes showed complete switches in the dominant transcription start site (TSS) or splice isoform, and we observed more subtle shifts in 1,304 other genes. These results suggest that Cufflinks can illuminate the substantial regulatory flexibility and complexity in even this well-studied model of muscle development and that it can improve transcriptome-based genome annotation.
Calcium signalling in astrocytes couples changes in neural activity to alterations in cerebral blood flow by eliciting vasoconstriction or vasodilation of arterioles. However, the mechanism for how ...these opposite astrocyte influences provide appropriate changes in vessel tone within an environment that has dynamic metabolic requirements remains unclear. Here we show that the ability of astrocytes to induce vasodilations over vasoconstrictions relies on the metabolic state of the rat brain tissue. When oxygen availability is lowered and astrocyte calcium concentration is elevated, astrocyte glycolysis and lactate release are maximized. External lactate attenuates transporter-mediated uptake from the extracellular space of prostaglandin E(2), leading to accumulation and subsequent vasodilation. In conditions of low oxygen concentration extracellular adenosine also increases, which blocks astrocyte-mediated constriction, facilitating dilation. These data reveal the role of metabolic substrates in regulating brain blood flow and provide a mechanism for differential astrocyte control over cerebrovascular diameter during different states of brain activation.
Black men, underrepresented in engineering, constitute a missing segment of the population who could contribute to the global knowledge economy. To address this national concern, stakeholders need ...additional research on strategies that aid in Black men's persistence. This study explores the experiences of 30 Black men in engineering graduate programs. Three factors are identified as helping them persist from year to year, and in many cases through completion of the doctorate: the role of family, spirituality and faith-based community, and undergraduate mentors. The article concludes with implications for future research and professional practice that may improve the experiences of Black men in engineering graduate programs, which may also increase the chances that they will remain in the engineering workforce.
Levels of amyloid β peptide 42 (Aβ42), total tau, and phosphorylated tau-181 are well-established cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease, but variability in manual plate-based ...assays has limited their use. We examined the relationship between CSF biomarkers, as measured by a novel automated immunoassay platform, and amyloid positron emission tomography.
CSF samples from 200 individuals underwent separate analysis for Aβ42, total tau, and phosphorylated tau-181 with automated Roche Elecsys assays. Aβ40 was measured with a commercial plate-based assay. Positron emission tomography with Pittsburgh Compound B was performed less than 1 year from CSF collection.
Ratios of CSF biomarkers (total tau/Aβ42, phosphorylated tau-181/Aβ42, and Aβ42/Aβ40) best discriminated Pittsburgh Compound B–positive from Pittsburgh Compound B–negative individuals.
CSF biomarkers and amyloid positron emission tomography reflect different aspects of Alzheimer's disease brain pathology, and therefore, less-than-perfect correspondence is expected. Automated assays are likely to increase the utility of CSF biomarkers.
•Cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease were measured with the Roche Elecsys assays.•Total tau/Aβ42, phosphorylated tau-181/Aβ42, and Aβ42/Aβ40 best distinguished Pittsburgh Compound B positron emission tomography status.•All three CSF ratios were positive in 92% of Pittsburgh Compound B–positive individuals.•All three CSF ratios were negative in 81% of Pittsburgh Compound B–negative individuals.•CSF biomarkers may detect Alzheimer's disease pathology earlier than amyloid positron emission tomography.
We examined whether plasma β-amyloid (Aβ)42/Aβ40, as measured by a high-precision assay, accurately diagnosed brain amyloidosis using amyloid PET or CSF p-tau181/Aβ42 as reference standards.
Using an ...immunoprecipitation and liquid chromatography-mass spectrometry assay, we measured Aβ42/Aβ40 in plasma and CSF samples from 158 mostly cognitively normal individuals that were collected within 18 months of an amyloid PET scan.
Plasma Aβ42/Aβ40 had a high correspondence with amyloid PET status (receiver operating characteristic area under the curve AUC 0.88, 95% confidence interval CI 0.82-0.93) and CSF p-tau181/Aβ42 (AUC 0.85, 95% CI 0.79-0.92). The combination of plasma Aβ42/Aβ40, age, and
ε4 status had a very high correspondence with amyloid PET (AUC 0.94, 95% CI 0.90-0.97). Individuals with a negative amyloid PET scan at baseline and a positive plasma Aβ42/Aβ40 (<0.1218) had a 15-fold greater risk of conversion to amyloid PET-positive compared to individuals with a negative plasma Aβ42/Aβ40 (
= 0.01).
Plasma Aβ42/Aβ40, especially when combined with age and
ε4 status, accurately diagnoses brain amyloidosis and can be used to screen cognitively normal individuals for brain amyloidosis. Individuals with a negative amyloid PET scan and positive plasma Aβ42/Aβ40 are at increased risk for converting to amyloid PET-positive. Plasma Aβ42/Aβ40 could be used in prevention trials to screen for individuals likely to be amyloid PET-positive and at risk for Alzheimer disease dementia.
This study provides Class II evidence that plasma Aβ42/Aβ40 levels accurately determine amyloid PET status in cognitively normal research participants.
•We test a mechanistic model linking task activity and restFC dysfunction in AD.•This theorizes that altered restFC in AD disrupts activity flow across the brain.•The model transforms healthy into ...unhealthy activity via individual restFC patterns.•This reliably predicts task activity and related dysfunction in at-risk AD subjects.•We provide a theoretical basis for integrating restFC into AD biomarker development.
Alzheimer's disease (AD) is linked to changes in fMRI task activations and fMRI resting-state functional connectivity (restFC), which can emerge early in the illness timecourse. These fMRI correlates of unhealthy aging have been studied in largely separate subfields. Taking inspiration from neural network simulations, we propose a unifying mechanism wherein restFC alterations associated with AD disrupt the flow of activations between brain regions, leading to aberrant task activations. We apply this activity flow model in a large sample of clinically normal older adults, which was segregated into healthy (low-risk) and at-risk subgroups based on established imaging (positron emission tomography amyloid) and genetic (apolipoprotein) AD risk factors. Modeling the flow of healthy activations over at-risk AD connectivity effectively transformed the healthy aged activations into unhealthy (at-risk) aged activations. This enabled reliable prediction of at-risk AD task activations, and these predicted activations were related to individual differences in task behavior. These results support activity flow over altered intrinsic functional connections as a mechanism underlying Alzheimer's-related dysfunction, even in very early stages of the illness. Beyond these mechanistic insights, this approach raises clinical potential by enabling prediction of task activations and associated cognitive dysfunction in individuals without requiring them to perform in-scanner cognitive tasks.
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