Loneliness and biomarkers of Alzheimer's disease, axonal damage, and astrogliosis: A coordinated analysis of two longitudinal cohorts.

Objectives: Loneliness is associated with an elevated risk of dementia. There is mixed evidence from imaging studies on whether loneliness is associated with neuropathology in dementia-free adults. This study tests whether loneliness is associated with plasma neurobiomarkers of amyloid (Aβ42/Aβ40), phosphorylated tau 181 (pTau181), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) and imaging measures of amyloid and tau.

Blood-Based Biomarkers and Risk of Onset of Mild Cognitive Impairment Over the Short and Long Term.

Background And Objectives: Blood-based biomarkers of amyloid and tau have been shown to predict Alzheimer disease (AD) dementia. Much less is known about their ability to predict risk of mild cognitive impairment (MCI), an earlier disease stage. This study examined whether levels of blood biomarkers of amyloid (Aβ/Aβ ratio), tau (p-tau), neurodegeneration (NfL), and glial activation and neuroinflammation (glial fibrillary acidic protein [GFAP], YKL40, soluble triggering receptor expressed on myeloid cells 2 [sTREM2]) collected when participants were cognitively normal are associated with the time to onset of MCI.

White matter free water mediates the associations between placental growth factor, white matter hyperintensities, and cognitive status.

Introduction: Placental growth factor (PlGF) may regulate cerebrovascular permeability. We hypothesized that white matter interstitial fluid accumulation, estimated via magnetic resonance imaging (MRI) free water (FW), would explain the associations between elevated PlGF, white matter hyperintensities (WMH), and cognitive impairment.

Methods: MarkVCID consortium participants ≥55 years old with plasma PlGF and brain MRI were included.

Sex differences in the trajectories of plasma biomarkers, brain atrophy, and cognitive decline relative to amyloid onset.

Introduction: The factors that influence the progression of Alzheimer's disease (AD) after individuals become amyloid-positive are poorly understood. This study examines how sex influences the longitudinal trajectories of plasma AD and neurodegenerative biomarkers in the years following a person's estimated onset of amyloid-β.

Methods: Linear mixed-effects modeling investigated overall and sex-specific longitudinal trajectories of plasma biomarkers, brain volumes, and cognition relative to the estimated age of amyloid onset in a cohort of 78 amyloid-positive Baltimore Longitudinal Study of Aging (BLSA) participants (n = 45 male; follow-up time: 6.

Preoperative Neurofilament Light Associated With Postoperative Delirium in Hip Fracture Repair Patients Without Dementia.

Background: Delirium commonly occurs in older adults following surgery; although its pathophysiology is not fully understood, underlying neurodegeneration is a risk factor.

Objective: Examine the association of preoperative levels of markers of neuronal damage, neurofilament light (NfL) and phosphorylated tau (p-tau), with postoperative delirium.

Methods: Preoperative cerebrospinal fluid (CSF) and plasma were obtained from 158 patients undergoing hip fracture repair and enrolled in the clinical trial "A STrategy to Reduce the Incidence of Postoperative Delirium in Elderly Patients.

Proteomic analysis of APOEε4 carriers implicates lipid metabolism, complement and lymphocyte signaling in cognitive resilience.

Background: Apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late onset Alzheimer's disease (AD). This case-cohort study used targeted plasma biomarkers and large-scale proteomics to examine the biological mechanisms that allow some APOEε4 carriers to maintain normal cognitive functioning in older adulthood.

Methods: APOEε4 carriers and APOEε3 homozygotes enrolled in the Women's Health Initiative Memory Study (WHIMS) from 1996 to 1999 were classified as resilient if they remained cognitively unimpaired beyond age 80, and as non-resilient if they developed cognitive impairment before or at age 80.

Acceleration of Brain Atrophy and Progression From Normal Cognition to Mild Cognitive Impairment.

Importance: It remains unclear which risk factors accelerate brain atrophy along with a progression from normal cognition to mild cognitive impairment (MCI).

Objective: To examine risk factors associated with the acceleration of brain atrophy and progression from normal cognition to MCI based on long-term longitudinal data for middle-aged and older adults.

Design, Setting, And Participants: Data for this cohort study were extracted from the Biomarkers for Older Controls at Risk for Dementia (BIOCARD) cohort, initiated at the National Institutes of Health from January 1, 1995, to December 31, 2005, and continued at Johns Hopkins University from January 1, 2015, to October 31, 2023.

Proteomics identifies potential immunological drivers of postinfection brain atrophy and cognitive decline.

Infections have been associated with the incidence of Alzheimer disease and related dementias, but the mechanisms responsible for these associations remain unclear. Using a multicohort approach, we found that influenza, viral, respiratory, and skin and subcutaneous infections were associated with increased long-term dementia risk. These infections were also associated with region-specific brain volume loss, most commonly in the temporal lobe.

Proteomic analyses reveal plasma EFEMP1 and CXCL12 as biomarkers and determinants of neurodegeneration.

Introduction: Plasma proteomic analyses of unique brain atrophy patterns may illuminate peripheral drivers of neurodegeneration and identify novel biomarkers for predicting clinically relevant outcomes.

Methods: We identified proteomic signatures associated with machine learning-derived aging- and Alzheimer's disease (AD) -related brain atrophy patterns in the Baltimore Longitudinal Study of Aging (n = 815). Using data from five cohorts, we examined whether candidate proteins were associated with AD endophenotypes and long-term dementia risk.

Molecular signatures of normal pressure hydrocephalus: a large-scale proteomic analysis of cerebrospinal fluid.

Given the persistent challenge of differentiating idiopathic Normal Pressure Hydrocephalus (iNPH) from similar clinical entities, we conducted an in-depth proteomic study of cerebrospinal fluid (CSF) in 28 shunt-responsive iNPH patients, 38 Mild Cognitive Impairment (MCI) due to Alzheimer's disease, and 49 healthy controls. Utilizing the Olink Explore 3072 panel, we identified distinct proteomic profiles in iNPH that highlight significant downregulation of synaptic markers and cell-cell adhesion proteins. Alongside vimentin and inflammatory markers upregulation, these results suggest ependymal layer and transependymal flow dysfunction.

Proteome-wide analysis identifies plasma immune regulators of amyloid-beta progression.

While immune function is known to play a mechanistic role in Alzheimer's disease (AD), whether immune proteins in peripheral circulation influence the rate of amyloid-β (Aβ) progression - a central feature of AD - remains unknown. In the Baltimore Longitudinal Study of Aging, we quantified 942 immunological proteins in plasma and identified 32 (including CAT [catalase], CD36 [CD36 antigen], and KRT19 [keratin 19]) associated with rates of cortical Aβ accumulation measured with positron emission tomography (PET). Longitudinal changes in a subset of candidate proteins also predicted Aβ progression, and the mid- to late-life (20-year) trajectory of one protein, CAT, was associated with late-life Aβ-positive status in the Atherosclerosis Risk in Communities (ARIC) study.

MRI-Based Prediction of Clinical Improvement after Ventricular Shunt Placement for Normal Pressure Hydrocephalus: Development and Evaluation of an Integrated Multisequence Machine Learning Algorithm.

Background And Purpose: Symptoms of normal pressure hydrocephalus (NPH) are sometimes refractory to shunt placement, with limited ability to predict improvement for individual patients. We evaluated an MRI-based artificial intelligence method to predict postshunt NPH symptom improvement.

Materials And Methods: Patients with NPH who underwent MRI before shunt placement at a single center (2014-2021) were identified.

Wearable Mechatronic Ultrasound-integrated AR Navigation System for Lumbar Puncture Guidance.

As one of the most commonly performed spinal interventions in routine clinical practice, lumbar punctures are usually done with only hand palpation and trial-and-error. Failures can prolong procedure time and introduce complications such as cerebrospinal fluid leaks and headaches. Therefore, an effective needle insertion guidance method is desired.

Assessment of Preanalytical Cerebrospinal Fluid Handling and Storage Factors on Measurement of Aβ1-42, Aβ1-40, and pTau181 Using an Automated Chemiluminescent Platform.

Background: Standardizing cerebrospinal fluid (CSF) laboratory protocols will improve the reliability and availability of clinical biomarker testing required for prescription of novel Alzheimer disease (AD) therapies. This study evaluated several preanalytical handling and storage factors common to β-amyloid1-42 (Aβ1-42), β-amyloid1-40 (Aβ1-40), and phosphorylated tau (pTau181) concentrations including storage at different temperatures, extended cap contact, various mixing methods, and multiple freeze-thaw cycles.

Methods: Aβ1-42, Aβ1-40, and pTau181 concentrations were measured using LUMIPULSE G1200 automated assays.

Alzheimer's and neurodegenerative disease biomarkers in blood predict brain atrophy and cognitive decline.

Background: Although blood-based biomarkers have been identified as cost-effective and scalable alternatives to PET and CSF markers of neurodegenerative disease, little is known about how these biomarkers predict future brain atrophy and cognitive decline in cognitively unimpaired individuals. Using data from the Baltimore Longitudinal Study of Aging (BLSA), we examined whether plasma biomarkers of Alzheimer's disease (AD) pathology (amyloid-β [Aβ], phosphorylated tau [pTau-181]), astrogliosis (glial fibrillary acidic protein [GFAP]), and neuronal injury (neurofilament light chain [NfL]) were associated with longitudinal brain volume loss and cognitive decline. Additionally, we determined whether sex, APOEε4 status, and plasma amyloid-β status modified these associations.

Plasma p-tau212 antemortem diagnostic performance and prediction of autopsy verification of Alzheimer's disease neuropathology.

Blood phosphorylated tau (p-tau) biomarkers, including p-tau217, show high associations with Alzheimer's disease (AD) neuropathologic change and clinical stage. Certain plasma p-tau217 assays recognize tau forms phosphorylated additionally at threonine-212, but the contribution of p-tau212 alone to AD is unknown. We developed a blood-based immunoassay that is specific to p-tau212 without cross-reactivity to p-tau217.

Molecular Signatures of Normal Pressure Hydrocephalus: A Largescale Proteomic Analysis of Cerebrospinal Fluid.

Given the persistent challenge of differentiating idiopathic Normal Pressure Hydrocephalus (iNPH) from similar clinical entities, we conducted an in-depth proteomic study of cerebrospinal fluid (CSF) in 28 shunt-responsive iNPH patients, 38 Mild Cognitive Impairment (MCI) due to Alzheimer's disease, and 49 healthy controls. Utilizing the Olink Explore 3072 panel, we identified distinct proteomic profiles in iNPH that highlight significant downregulation of synaptic markers and cell-cell adhesion proteins. Alongside vimentin and inflammatory markers upregulation, these results suggest ependymal layer and transependymal flow dysfunction.

CO cerebrovascular reactivity measured with CBF-MRI in older individuals: Association with cognition, physical function, amyloid and tau proteins.

Vascular pathology is the second leading cause of cognitive impairment and represents a major contributing factor in mixed dementia. However, biomarkers for vascular cognitive impairment and dementia (VCID) are under-developed. Here we aimed to investigate the potential role of CO2 Cerebrovascular Reactivity (CVR) measured with phase-contrast quantitative flow MRI in cognitive impairment and dementia.

VICTR: Venous transit time imaging by changes in T relaxation.

Purpose: Abnormalities in cerebral veins are a common finding in many neurological diseases, yet there is a scarcity of MRI techniques to assess venous hemodynamic function. The present study aims to develop a noncontrast technique to measure a novel blood flow circulatory measure, venous transit time (VTT), which denotes the time it takes for water to travel from capillary to major veins.

Methods: The proposed sequence, venous transit time imaging by changes in T relaxation (VICTR), is based on the notion that as water molecules transition from the tissue into the veins, they undergo a change in T relaxation time.

Neuronal pentraxin 2 correlates with neurodegeneration but not cognition in idiopathic normal pressure hydrocephalus (iNPH).

Aim Of The Study: Neuronal pentraxin-2 (NPTX2) is a synaptic protein responsible for modulating plasticity at excitatory synapses. While the role of NPTX2 as a novel synaptic biomarker in cognitive disorders has been elucidated recently, its role in idiopathic normal pressure hydrocephalus (iNPH) is not yet understood.

Clinical Rationale For Study: To determine if NPTX2 predicts cognition in patients with iNPH, and whether it could serve as a predictive marker for shunt outcomes.