Association of plasma Alzheimer's disease biomarkers with cognitive decline in cognitively unimpaired individuals.

Introduction: Plasma biomarkers' utility for predicting incident mild cognitive impairment (MCI) remains unclear. We evaluated associations of plasma Alzheimer's disease (AD) biomarkers and amyloid positron emission tomography (PET) with transitions from cognitively unimpaired (CU) to MCI in the Mayo Clinic Study of Aging (MCSA) and BioFINDER-2 studies.

Methods: Associations of continuous baseline plasma biomarker levels and amyloid PET Centiloid with progression to MCI, adjusting for age, sex, and education, were evaluated with Cox proportional hazards models.

Analysis of imaging signatures in F-DOPA PET of glioblastoma treated with dose-escalated radiotherapy.

Background/objectives: F-DOPA is an amino acid radiotracer with high uptake in glioblastoma and low uptake in normal brain. Patients underwent pre-radiation and post-radiation F-DOPA PET scans on a prospective clinical trial. This analysis investigates quantitative image features correlated with prognosis and treatment response to identify patients who benefit the most from dose-escalated therapy.

Evaluation and interpretation of DTI-ALPS, a proposed surrogate marker for glymphatic clearance, in a large population-based sample.

Background: The diffusion tensor imaging along perivascular spaces index (DTI-ALPS), which measures diffusivity in the perivascular spaces along the medullary veins, has gained popularity and controversy as a surrogate marker of glymphatic clearance. The goal of this work is to automatically estimate DTI-ALPS in a large population-based sample, evaluate the correlates of the signal observed in the context of aging and dementia biomarkers, and evaluate its clinical usefulness.

Methods: We identified 2715 participants aged 30 + years in the population-based Mayo Clinic Study of Aging with diffusion MRI.

Evaluation of [F]F-CNBI and [F]F-CNPI PET Probes in GSK-3β Transgenic Mice.

The present study explores the noninvasive positron emission tomography (PET) imaging for the detection of GSK-3β overexpression using [F]F-CNPI and [F]F-CNBI in a GSK-3β overexpressing transgenic mouse model. Herein, we validated GSK-3β overexpression in different brain regions by genotyping and Western blot. PET scans and ex vivo biodistribution were performed in normal mice and early stage and late-stage GSK-3β transgenic mice with and without the P-gp inhibitor, Tariquidar.

Combating Genetic Heterogeneity for Polygenic Prediction of Susceptibility to Brain β-Amyloid Deposition: Beyond .

Background And Objectives: The (apolipoprotein E) ε4 allele is the strongest known genetic risk factor for sporadic Alzheimer disease (AD) and for brain amyloidosis, an early marker of disease pathophysiology. However, ε4 is present in only 25% of the general population and is by itself inadequate for explaining susceptibility to amyloid accumulation or AD diagnosis. Existing studies have been limited by potential confounding due to inclusion of individuals carrying ε4 or ε2 (which has a modest protective association).

Relationship between tau-PET and quantitative susceptibility mapping in atypical Alzheimer's disease.

Background: Iron is an important component in neurofibrillary tangles, is known to co-localize with tangles in Alzheimer's disease (AD) and can be measured using quantitative susceptibility mapping (QSM). However, it is unclear if iron measured using QSM is regionally related to tau in atypical presentations of AD.

Methods: Forty patients with atypical AD underwent a 3 T magnetic resonance imaging (MRI) scan with a five-echo gradient echo sequence to calculate QSM, Aβ, and [F] AV-1451 positron emission tomography (PET).

Discrepancies between CSF biomarker and PET determinations of elevated brain amyloid and their prognostic significance.

Introduction: When cerebrospinal fluid (CSF) and positron emission tomography (PET) measurements for amyloid-beta-peptide (Aβ) related pathology are discordant, therapeutic decision-making becomes uncertain.

Methods: Using data from patients with mild cognitive impairment (n = 541) from the Alzheimer's Disease Neuroimaging Initiative, we examined baseline characteristics and longitudinal clinical outcomes in persons grouped according to normal/abnormal Aβ via concurrent CSF and PET determinations using standard cutpoints.

Results: Discordant groups for brain Aβ status (CSF+/PET- and CSF-/PET+) each represented about 5% of the mild cognitive impairment (MCI) population.

Distinct 11C-ER176 PET Neuroinflammatory Profiles and Tau Colocalization in Progressive Apraxia of Speech With and Without Parkinson-plus Syndrome.

Background: Progressive apraxia of speech (PAOS) is a neurodegenerative disorder most commonly arising from a 4-repeat tauopathy that affects the programming or planning of speech, although many patients develop a Parkinson-plus syndrome. The role of neuroinflammation as a disease mechanism is unknown. We investigated the spatial pattern of neuroinflammation in PAOS using PET and evaluated whether it is associated with disease severity, presence of Parkinson-plus features, and tau PET uptake.

An FDG-PET-Based Machine Learning Framework to Support Neurologic Decision-Making in Alzheimer Disease and Related Disorders.

Background And Objectives: Distinguishing neurodegenerative diseases is a challenging task requiring neurologic expertise. Clinical decision support systems (CDSSs) powered by machine learning (ML) and artificial intelligence can assist with complex diagnostic tasks by augmenting user capabilities, but workflow integration poses many challenges. We propose that a modeling framework based on fluorodeoxyglucose PET (FDG-PET) imaging can address these challenges and form the basis of an effective CDSS for neurodegenerative disease.

Plasma NfL and GFAP for predicting VCI and related brain changes in community and clinical cohorts.

Introduction: We investigated the usefulness of plasma neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) for capturing vascular cognitive impairment (VCI) in the context of amyloidosis.

Methods: Using two independent cohorts (n = 1810), we assessed the relationship of plasma NfL and GFAP with (1) vascular brain indices; (2) diagnostic states using the following definitions: vascular versus not (white matter hyperintensity/total intracranial volume ≥ 1.3%), and cognitively impaired (CI) versus cognitively unimpaired (CU) using Clinical Dementia Rating ([CDR] scale ≥ 0.

Evaluation of disproportionately enlarged subarachnoid-space hydrocephalus in progressive supranuclear palsy.

Normal pressure hydrocephalus is typically defined by the triad of gait disturbance, cognitive impairment, and urinary incontinence, and is characterized on MRI by disproportionately enlarged subarachnoid-space. Gait disturbance is also a commonly reported symptom in Parkinsonian disorders, especially progressive supranuclear palsy, although the frequency, clinical significance and mechanisms of hydrocephalus in these disorders are unclear. We aimed to assess the prevalence of hydrocephalic MRI parameters in a large cohort of Parkinsonian disorders and evaluate associations with clinical features and abnormalities on MRI and PET.

Characterization of transcriptomic changes in the neurovascular unit of Alzheimiers transgenic mouse models using digital spatial profiling.

Alzheimer's disease (AD) affects 40 million individuals globally and is characterized by the accumulation of amyloid-beta (Aβ) proteins, which aggregate and form plaques. BBB dysfunction drives AD cerebrovascular pathology and BBB integrity is maintained by neurovascular unit (NVU). Specifically, within the NVU, the cerebral endothelial cells maintain vascular homeostasis.

Machine Learning Models of Voxel-Level [F] Fluorodeoxyglucose Positron Emission Tomography Data Excel at Predicting Progressive Supranuclear Palsy Pathology.

Objective: To determine whether a machine learning model of voxel level [f]fluorodeoxyglucose positron emission tomography (PET) data could predict progressive supranuclear palsy (PSP) pathology, as well as outperform currently available biomarkers.

Methods: One hundred and thirty-seven autopsied patients with PSP (n = 42) and other neurodegenerative diseases (n = 95) who underwent antemortem [f]fluorodeoxyglucose PET and 3.0 Tesla magnetic resonance imaging (MRI) scans were analyzed.

Amyloid beta peptides inhibit glucose transport at the blood-brain barrier by disrupting the insulin-AKT pathway.

Molecular mechanisms underlying disruptions in brain glucose uptake and metabolism, linked with cognitive decline in Alzheimer's disease (AD) patients, are only partially understood. This study investigated how soluble amyloid beta (sAβ) peptides affect glucose transport at the blood-brain barrier (BBB), the primary portal for glucose entry into the brain. We demonstrated that [F]-fluorodeoxyglucose (FDG) uptake is reduced in sAβ overproducing APP,PS1 transgenic mice compared to wild-type mice.

Cortical microstructural abnormalities in dementia with Lewy bodies and their associations with Alzheimer's disease copathologies.

Dementia with Lewy bodies (DLB) frequently coexists with Alzheimer's disease pathology, yet the pattern of cortical microstructural injury and its relationship with amyloid, tau, and cerebrovascular pathologies remains unclear. We applied neurite orientation dispersion and density imaging (NODDI) to assess cortical microstructural integrity in 57 individuals within the DLB spectrum and 57 age- and sex-matched cognitively unimpaired controls by quantifying mean diffusivity (MD), tissue-weighted neurite density index (tNDI), orientation dispersion index (ODI), and free water fraction (FWF). Amyloid and tau levels were measured using PiB and Flortaucipir PET imaging.

Microglia positron emission tomography and progression in multiple sclerosis: thalamus on fire.

Increased innate immune activity promotes neurodegeneration and contributes to progression in multiple sclerosis. This prospective case-control study aims to investigate thalamic microglia density on 18kDa translocator protein PET in patients with multiple sclerosis using a third-generation radioligand, C-ER176, and investigate the associations of C-ER176 PET uptake with imaging and clinical measures of progression in multiple sclerosis. Patients with multiple sclerosis ( = 50) and controls ( = 55) were prospectively enrolled and they underwent C-ER176 PET and MRI including diffusion MRI with neurite orientation dispersion and density imaging.

Aβ and p-tau 181 as disease biomarkers in atypical Alzheimer's disease.

BackgroundStudies suggest that plasma Alzheimer's disease (AD) biomarkers may aid in the overall diagnosis of AD, but their utility among patients with atypical clinical presentations of AD are unknown.ObjectiveThe main objective of this study was to determine the relationship between amyloid-β (Aβ) and tau plasma biomarkers and PET measures of both Aβ and tau in atypical AD. The secondary objective was to determine if plasma biomarkers could differentiate patients with different atypical AD phenotypes and whether they were related to measures of disease severity.

Patterns of Factors in the National Institute on Aging Health Disparities Research Framework Domains and Mild Cognitive Impairment Risk.

Introduction: Alzheimer's disease and related dementias are public health and social care challenges. This study used the National Institute on Aging Health Disparities Research Framework to organize potential cognitive impairment risk factors. It aimed to examine patterns of environmental, sociocultural, behavioral, and biological factors and identify key components that predict mild cognitive impairment risk.

Relationships between hypometabolism and both β-amyloid and tau PET in corticobasal syndrome.

Introduction: Alzheimer's disease (AD) pathology causes corticobasal syndrome (CBS) in 21%-50% of patients. Studies have assessed hypometabolism in CBS according to β-amyloid (A) positron emission tomography (PET), but the understanding of the association of both AD-tau (T) and A with hypometabolism is incomplete.

Methods: Thirty-three CBS patients and 45 controls underwent fluorodeoxyglucose (FDG), flortaucipir, and Pittsburgh compound-B PET and were classified as A± and T±.

Genome-wide association study of neuropathological features in Lewy body disease.

Studies assessing genetic associations with neuropathological features in Lewy body disease (LBD) have been limited to candidate gene investigations, and therefore, information is lacking regarding the genetic architecture of the neuropathology of LBD. In the current study, we examined a large series of neuropathologically confirmed LBD cases (n = 980 in the discovery series, n = 503 in the replication series) and performed genome-wide association studies of 11 different neuropathological outcome measures. The 11 neuropathological outcomes included Braak neurofibrillary tangle (NFT) stage, Thal amyloid phase, LBD subtype, Lewy body (LB) counts in five different brain regions, dorsolateral and ventromedial putaminal tyrosine hydroxylase immunoreactivity and neuronal loss in the ventrolateral part of the substantia nigra.

High resolution autoradiography of [F]MK-6240 and [F]Flortaucipir shows similar neurofibrillary tangle binding patterns preferentially recognizing middling neurofibrillary tangle maturity.

Recent developments in tau positron emission tomography (PET) radiotracers have enhanced the visualization of tau aggregates in Alzheimer's disease (AD). The maturity level of neurofibrillary tangles can affect its recognition by biomarkers. Early detection of tau aggregates regarding tangle pathology is of interest in early diagnosis and comparison of tau radiotracers in this aspect is important.

White matter hyperintensities in dementia with lewy bodies and posterior cortical atrophy.

Dementia with Lewy bodies (DLB) and posterior cortical atrophy (PCA) are neurodegenerative disorders that can overlap clinically and in patterns of regional hypometabolism and show elevated white matter hyperintensity (WMH) burden. Little is known about the regional WMH burden in DLB patients without any interference of AD pathology and how these patterns compare to PCA patients. Twenty-two amyloid-negative DLB patients, 40 amyloid-positive PCA patients, and 49 amyloid-negative cognitively unimpaired (CU) healthy individuals were recruited at Mayo Clinic, Rochester, MN.

Plasma Alzheimer's disease biomarker relationships with incident abnormal amyloid PET.

Introduction: Limited data exist on the utility of plasma biomarkers to predict incident abnormal amyloid positron emission tomography (PET). In this study we evaluate the association of plasma Alzheimer's disease (AD) biomarkers with amyloid PET progression among initially amyloid PET negative (A-) individuals.

Methods: We included 290 A-, cognitively unimpaired Mayo Clinic Study of Aging participants.