Plasma Total-Tau and Neurofilament Light Chain as Diagnostic Biomarkers of Alzheimer's Disease Dementia and Mild Cognitive Impairment in Adults with Down Syndrome.

BACKGROUND: The need for diagnostic biomarkers of cognitive decline is particularly important among aging adults with Down syndrome (DS). Growing empirical support has identified the utility of plasma derived biomarkers among neurotypical adults with mild cognitive impairment (MCI) and Alzheimer's disease (AD); however, the application of such biomarkers has been limited among the DS population. OBJECTIVE: This study aimed to investigate the cross-sectional diagnostic performance of plasma neurofilament light chain (Nf-L) and total-tau, individually and in combination among a cohort of DS adults. METHODS: Plasma samples were analyzed from n = 305 (n = 225 cognitively stable (CS); n = 44 MCI-DS; n = 36 DS-AD) participants enrolled in the Alzheimer's Biomarker Consortium -Down Syndrome. RESULTS: In distinguishing DS-AD participants from CS, Nf-L alone produced an AUC of 90%, total-tau alone reached 74%, and combined reached an AUC of 86%. When age and gender were included, AUC increased to 93%. Higher values of Nf-L, total-tau, and age were all shown to be associated with increased risk for DS-AD. When distinguishing MCI-DS participants from CS, Nf-L alone produced an AUC of 65%, while total-tau alone reached 56%. A combined model with Nf-L, total-tau, age, and gender produced an AUC of 87%. Both higher values in age and total-tau were found to increase risk for MCI-DS; Nf-L levels were not associated with increased risk for MCI-DS. CONCLUSION: Advanced assay techniques make total-tau and particularly Nf-L useful biomarkers of both AD pathology and clinical status in DS and have the potential to serve as outcome measures in clinical trials for future disease-modifying drugs.

Relationship of Neurofilament Light (NfL) and Cognitive Performance in a Sample of Mexican Americans with Normal Cognition, Mild Cognitive Impairment and Dementia.

INTRODUCTION: This study characterized the relationship between plasma NfL and cognition in a community-based sample of older Mexican Americans. METHODS: 544 participants completed a battery of neuropsychological tests and were diagnosed using clinical criteria. NfL was assayed using Simoa. NfL levels across groups and tests were analyzed. RESULTS: Difference in NfL was found between normal and impaired groups and was related to global cognition, processing speed, executive functions and a list of learning tasks with a significant negative effect for all diagnostic groups. NfL had a negative impact on processing speed, attention, executive functions and delayed and recognition memory for both normal and MCI groups. CONCLUSION: The research supports plasma NfL as a marker of cognitive impairment related to neurodegenerative processes in Mexican Americans and may be a marker of early changes in cognition in those with normal cognition and at risk for developing MCI.

Assessing Neuronal and Astrocyte Derived Exosomes From Individuals With Mild Traumatic Brain Injury for Markers of Neurodegeneration and Cytotoxic Activity.

Mild traumatic brain injury (mTBI) disproportionately affects military service members and is very difficult to diagnose. To-date, there is currently no blood-based, diagnostic biomarker for mTBI cases with persistent post concussive symptoms. To examine the potential of neuronally-derived (NDE) and astrocytic-derived (ADE) exosome cargo proteins as biomarkers of chronic mTBI in younger adults, we examined plasma exosomes from a prospective longitudinal study of combat-related risk and resilience, marine resiliency study II (MRSII). After return from a combat-deployment participants were interviewed to assess TBI exposure while on deployment. Plasma exosomes from military service members with mTBI (mean age, 21.7 years, n = 19, avg. days since injury 151), and age-matched, controls (deployed service members who did not endorse a deployment-related TBI or a pre-deployment history of TBI; mean age, 21.95 years, n = 20) were precipitated and enriched against a neuronal adhesion protein, L1-CAM, and an astrocyte marker, glutamine aspartate transporter (GLAST) using magnetic beads to immunocapture the proteins and subsequently selected by fluorescent activated cell sorting (FACS). Extracted protein cargo from NDE and ADE preparations were quantified for protein levels implicated in TBI neuropathology by standard ELISAs and on the ultra-sensitive single molecule assay (Simoa) platform. Plasma NDE and ADE levels of Aß42 were significantly higher while plasma NDE and ADE levels of the postsynaptic protein, neurogranin (NRGN) were significantly lower in participants endorsing mTBI exposure compared to controls with no TBI history. Plasma NDE and ADE levels of Aß40, total tau, and neurofilament light (NFL), P-T181-tau, P-S396-tau were either undetectable or not significantly different between the two groups. In an effort to understand the pathogenetic potential of NDE and ADE cargo proteins, neuron-like cultures were treated with NDE and ADE preparations from TBI and non-TBI groups. Lastly, we determined that plasma NDE but not ADE cargo proteins from mTBI samples were found to be toxic to neuron-like recipient cells in vitro. These data support the presence of markers of neurodegeneration in NDEs of mTBI and suggest that these NDEs can be used as tools to identify pathogenic mechanisms of TBI.

A proteomic signature for dementia with Lewy bodies.

INTRODUCTION: We sought to determine if a proteomic profile approach developed to detect Alzheimer's disease would distinguish patients with Lewy body disease from normal controls, and if it would distinguish dementia with Lewy bodies (DLB) from Parkinson's disease (PD). METHODS: Stored plasma samples were obtained from 145 patients (DLB n = 57, PD without dementia n = 32, normal controls n = 56) enrolled from patients seen in the Behavioral Neurology or Movement Disorders clinics at the Mayo Clinic, Florida. Proteomic assays were conducted and analyzed as per our previously published protocols. RESULTS: In the first step, the proteomic profile distinguished the DLB-PD group from controls with a diagnostic accuracy of 0.97, sensitivity of 0.91, and specificity of 0.86. In the second step, the proteomic profile distinguished the DLB from PD groups with a diagnostic accuracy of 0.92, sensitivity of 0.94, and specificity of 0.88. DISCUSSION: These data provide evidence of the potential utility of a multitiered blood-based proteomic screening method for detecting DLB and distinguishing DLB from PD.

A potent antioxidant small molecule aimed at targeting metal-based oxidative stress in neurodegenerative disorders.

Metal-ion misregulation and oxidative stress have been linked to the progressive neurological decline associated with multiple neurodegenerative disorders. Transition metal-mediated oxidation of biomolecules via Fenton chemical reactions plays a role in disease progression. Herein we report the synthesis, characterization and antioxidant activity of 2; a pyclen derivative with enhanced antioxidant character.