Multimodal neuroimaging biomarkers and subtle cognitive decline in a population-based cohort without dementia.

Background: The relationship between subtle cognitive decline and Alzheimer's disease (AD) pathology as measured by biomarkers in settings outside of specialty memory clinics is not well characterized.

Objective: To investigate how subtle longitudinal cognitive decline relates to neuroimaging biomarkers in individuals drawn from a population-based study in an economically depressed, small-town area in southwestern Pennsylvania, USA.

Methods: A subset of participants without dementia (N = 115, age 76.

Where Do Plasma Biomarkers fit in With Current Alzheimer's Disease Detection?

Objectives: We examine the clinical utility of plasma-based detection for Alzheimer's disease (AD) pathophysiology in older adults with mild cognitive impairment (MCI) and whether cognitive screening can inform when to use plasma-based AD tests.

Methods: Seventy-four community-dwelling older adults with MCI had testing with plasma phosphorylated tau (p-tau) 217 and 181, positron emission tomography (PET) imaging for amyloid beta (Aβ), and cognitive assessment. Receiver operating characteristic (ROC) analysis was used to assess the diagnostic value of plasma p-tau.

Higher Striatal Dopamine is Related With Lower Physical Performance Fatigability in Community-Dwelling Older Adults.

Background: Fatigability in community-dwelling older adults is highly prevalent and disabling, but lacks a treatment. Greater nigrostriatal dopaminergic signaling can ameliorate performance fatigability in healthy young adults, but its role in community-dwelling older adults is not known. We hypothesized that higher nigrostriatal dopaminergic integrity would be associated with lower performance fatigability, independent of cardiopulmonary and musculoskeletal energetics and other health conditions.

A preliminary investigation of worry, cortical amyloid burden, and stressor-evoked brain and cardiovascular reactivity in older adults.

Worry is a transdiagnostic symptom common to many neurocognitive disorders of aging, including early stages of Alzheimer's disease and related dementias (ADRD). Severe worry is associated with amyloid burden in cognitively intact older adults, yet the mechanisms underlying this association are not well understood. We hypothesize that this relationship involves altered brain and cardiovascular reactivity to acute stressors, a brain-body phenotype that also increases risk for cardiovascular disease.

Implementation and Assessment of Tau Thresholds in Non-Demented Individuals as Predictors of Cognitive Decline in Tau Imaging Studies.

Background: Tau accumulation in Alzheimer's disease is associated with short term clinical progression and faster rates of cognitive decline in individuals with high amyloid-β deposition. Defining an optimal threshold of tau accumulation predictive of cognitive decline remains a challenge.

Objective: We tested the ability of regional tau PET sensitivity and specificity thresholds to predict longitudinal cognitive decline.

Harmonizing tau positron emission tomography in Alzheimer's disease: The CenTauR scale and the joint propagation model.

Introduction: Tau-positron emission tomography (PET) outcome data of patients with Alzheimer's disease (AD) cannot currently be meaningfully compared or combined when different tracers are used due to differences in tracer properties, instrumentation, and methods of analysis.

Methods: Using head-to-head data from five cohorts with tau PET radiotracers designed to target tau deposition in AD, we tested a joint propagation model (JPM) to harmonize quantification (units termed "CenTauR" [CTR]). JPM is a statistical model that simultaneously models the relationships between head-to-head and anchor point data.

Ligand-based design of [F]OXD-2314 for PET imaging in non-Alzheimer's disease tauopathies.

Positron emission tomography (PET) imaging of tau aggregation in Alzheimer's disease (AD) is helping to map and quantify the in vivo progression of AD pathology. To date, no high-affinity tau-PET radiopharmaceutical has been optimized for imaging non-AD tauopathies. Here we show the properties of analogues of a first-in-class 4R-tau lead, [F]OXD-2115, using ligand-based design.

Kinetic modeling of the monoamine oxidase-B radioligand [F]SMBT-1 in human brain with positron emission tomography.

This paper describes pharmacokinetic analyses of the monoamine-oxidase-B (MAO-B) radiotracer [F]()-(2-methylpyrid-5-yl)-6-[(3-fluoro-2-hydroxy)propoxy]quinoline ([F]SMBT-1) for positron emission tomography (PET) brain imaging. Brain MAO-B expression is widespread, predominantly within astrocytes. Reactive astrogliosis in response to neurodegenerative disease pathology is associated with MAO-B overexpression.

Apolipoprotein E and Alzheimer's disease pathology in African American older adults.

The apolipoprotein-E4 (APOE*4) and apolipoprotein-E2 (APOE*2) alleles are more common in African American versus non-Hispanic white populations, but relationships of both alleles with Alzheimer's disease (AD) pathology among African American individuals are unclear. We measured APOE allele and β-amyloid (Aβ) and tau using blood samples and positron emission tomography (PET) images, respectively. Individual regression models tested associations of each APOE allele with Aβ or tau PET overall, stratified by racialized group, and with a racialized group interaction.

Association Between β-Amyloid Accumulation and Incident Dementia in Individuals 80 Years or Older Without Dementia.

Background And Objectives: While the highest prevalence of dementia occurs in individuals older than 80 years, most imaging studies focused on younger populations. The rates of β-amyloid (Aβ) accumulation and the effect of Alzheimer disease (AD) pathology on progression to dementia in this age group remain unexplored. In this study, we examined the relationship between changes in Aβ deposition over time and incident dementia in nondemented individuals followed during a period of 11 years.

Sex-dependent alterations in hippocampal connectivity are linked to cerebrovascular and amyloid pathologies in normal aging.

Introduction: Compared to males, females have an accelerated trajectory of cognitive decline in Alzheimer's disease (AD). The neurobiological factors underlying the more rapid cognitive decline in AD in females remain unclear. This study explored how sex-dependent alterations in hippocampal connectivity over 2 years are associated with cerebrovascular and amyloid pathologies in normal aging.

Low thalamic activity during a digit-symbol substitution task is associated with symptoms of subjective cognitive decline.

Introduction: Subjective cognitive decline (SCD) may represent the earliest preclinical stage of Alzheimer's Disease (AD) for some older adults. However, the underlying neurobiology of SCD is not completely understood. Since executive function may be affected earlier than memory function in the progression of AD, we aimed to characterize SCD symptoms in terms of fMRI brain activity during the computerized digit-symbol substitution task (DSST), an executive function task.

Biostatistical Estimation of Tau Threshold Hallmarks (BETTH) Algorithm for Human Tau PET Imaging Studies.

A methodology for determining tau PET thresholds is needed to confidently detect early tau deposition. We compared multiple threshold-determining methods in participants who underwent either F-flortaucipir or F-MK-6240 PET scans. F-flortaucipir ( = 798) and F-MK-6240 ( = 216) scans were processed and sampled to obtain regional SUV ratios.

CenTauR: Toward a universal scale and masks for standardizing tau imaging studies.

Introduction: Recently, an increasing number of tau tracers have become available. There is a need to standardize quantitative tau measures across tracers, supporting a universal scale. We developed several cortical tau masks and applied them to generate a tau imaging universal scale.

Identifying sex-specific risk architectures for predicting amyloid deposition using neural networks.

In older adults without dementia, White Matter Hyperintensities (WMH) in MRI have been shown to be highly associated with cerebral amyloid deposition, measured by the Pittsburgh compound B (PiB) PET. However, the relation to age, sex, and education in explaining this association is not well understood. We use the voxel counts of regional WMH, age, one-hot encoded sex, and education to predict the regional PiB using a multilayer perceptron with only rectilinear activations using mean squared error.

Identification of a Putative α-synuclein Radioligand Using an in silico Similarity Search.

Purpose: Previous studies from our lab utilized an ultra-high throughput screening method to identify compound 1 as a small molecule that binds to alpha-synuclein (α-synuclein) fibrils. The goal of the current study was to conduct a similarity search of 1 to identify structural analogs having improved in vitro binding properties for this target that could be labeled with radionuclides for both in vitro and in vivo studies for measuring α-synuclein aggregates.

Methods: Using 1 as a lead compound in a similarity search, isoxazole derivative 15 was identified to bind to α-synuclein fibrils with high affinity in competition binding assays.

The Association of Age-Related and Off-Target Retention with Longitudinal Quantification of [F]MK6240 Tau PET in Target Regions.

6-(fluoro-F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine ([F]MK6240) tau PET tracer quantifies the brain tau neurofibrillary tangle load in Alzheimer disease. The aims of our study were to test the stability of common reference region estimates in the cerebellum over time and across diagnoses and evaluate the effects of age-related and off-target retention on the longitudinal quantification of [F]MK6240 in target regions. We assessed reference, target, age-related, and off-target regions in 125 individuals across the aging and Alzheimer disease spectrum with longitudinal [F]MK6240 SUVs and SUV ratios (SUVRs) (mean ± SD, 2.

In Pre-Clinical AD Small Vessel Disease is Associated With Altered Hippocampal Connectivity and Atrophy.

Objective: Small Vessel Disease (SVD) is known to be associated with higher AD risk, but its relationship to amyloidosis in the progression of AD is unclear. In this cross-sectional study of cognitively normal older adults, we explored the interactive effects of SVD and amyloid-beta (Aβ) pathology on hippocampal functional connectivity during an associative encoding task and on hippocampal volume.

Methods: This study included 61 cognitively normal older adults (age range: 65-93 years, age mean ± standard deviation: 75.

Beyond monoamines: II. Novel applications for PET imaging in psychiatric disorders.

Early applications of positron emission tomography (PET) in psychiatry sought to identify derangements of cerebral blood flow and metabolism. The need for more specific neurochemical imaging probes was soon evident, and these probes initially targeted the sites of action of neuroleptic (dopamine D receptors) and psychoactive (serotonin receptors) drugs. For nearly 30 years, the centrality of monoamine dysfunction in psychiatric disorders drove the development of an armamentarium of monoaminergic PET radiopharmaceuticals and imaging methodologies.

Association between lower body temperature and increased tau pathology in cognitively normal older adults.

Background: Preclinical studies suggest body temperature (Tb) and consequently brain temperature has the potential to bidirectionally interact with tau pathology in Alzheimer's Disease (AD). Tau phosphorylation is substantially increased by a small (<1 °C) decrease in temperature within the human physiological range, and thermoregulatory nuclei are affected by tau pathology early in the AD continuum. In this study we evaluated whether Tb (as a proxy for brain temperature) is cross-sectionally associated with clinically utilized markers of tau pathology in cognitively normal older adults.

Beyond monoamines: I. Novel targets and radiotracers for Positron emission tomography imaging in psychiatric disorders.

With the emergence of positron emission tomography (PET) in the late 1970s, psychiatry had access to a tool capable of non-invasive assessment of human brain function. Early applications in psychiatry focused on identifying characteristic brain blood flow and metabolic derangements using radiotracers such as [ O]H O and [ F]FDG. Despite the success of these techniques, it became apparent that more specific probes were needed to understand the neurochemical bases of psychiatric disorders.

Brain health correlates of mobility-related confidence.

Background: Mobility is important for independence in older age. While brain health correlates of objectively measured mobility-related features like gait and balance have been reported, we aimed to test neuroimaging and cognitive correlates of subjective measures of mobility-related confidence.

Methods: We carried out a cross-sectional observational study comprised of N = 29 cognitively unimpaired older adult participants, mean age 75.

First-in-Humans Evaluation of F-SMBT-1, a Novel F-Labeled Monoamine Oxidase-B PET Tracer for Imaging Reactive Astrogliosis.

Reactive gliosis, characterized by reactive astrocytes and activated microglia, contributes greatly to neurodegeneration throughout the course of Alzheimer disease (AD). Reactive astrocytes overexpress monoamine oxidase B (MAO-B). We characterized the clinical performance of F-()-(2-methylpyrid-5-yl)-6-[(3-fluoro-2-hydroxy)propoxy]quinoline (F-SMBT-1), a novel MAO-B PET tracer as a potential surrogate marker of reactive astrogliosis.

Comparing Pathological Risk Factors for Dementia between Cognitively Normal Japanese and Americans.

The Alzheimer's Disease Neuroimaging Initiative showed that Japanese had significantly lower brain Aβ burden than Americans among a cognitively normal population. This cross-sectional study aimed to compare vascular disease burden, Aβ burden, and neurodegeneration between cognitively normal elderly Japanese and Americans. Japanese and American participants were matched for age (±4-year-old), sex, and Apolipoprotein E () genotype.