[18F]PI-2620 Tau PET signal across the aging and Alzheimer's disease clinical spectrum.

[18F]PI-2620 is a second generation tracer that has shown high binding affinity for tau aggregation in Alzheimer's disease (AD). However, [18F]PI-2620 signal in a large sample spanning the healthy aging and AD clinical spectrum as well as the stability of signal across different acquisition time windows has not yet been examined. Here, amyloid negative (Aβ-) cognitively unimpaired (CU; n = 49), amyloid positive (Aβ+) CU (n = 37), CU individuals with unknown amyloid status (n = 5), mild cognitive impairment (MCI; n = 14), dementia due to AD (n = 19), and non-AD neurodegenerative disorder (n = 54) participants were scanned with [18F]PI-2620 using a 45-75 min and/or 60-90 min acquisition time window.

Synergistic effects of ε4 and Alzheimer's pathology on the neural correlates of episodic remembering in cognitively unimpaired older adults.

Amyloid-β (Aβ) and tau pathology begin accumulating decades before clinical symptoms and are influenced by ε4, a key genetic risk factor for Alzheimer's disease (AD). Although the presence of Aβ, tau, and ε4 are thought to impact brain function, their effects on the neural correlates of episodic memory retrieval in preclinical AD remains unknown. We investigated this question in 159 cognitively unimpaired older adults (mean age, 68.

Disruption of the cerebrospinal fluid-plasma protein balance in cognitive impairment and aging.

The brain barrier system, including the choroid plexus, meninges and brain vasculature, regulates substrate transport and maintains differential protein concentrations between blood and cerebrospinal fluid (CSF). Aging and neurodegeneration disrupt brain barrier function, but proteomic studies of the effects on blood-CSF protein balance are limited. Here we used SomaScan proteomics to characterize paired CSF and plasma samples from 2,171 healthy or cognitively impaired older individuals from multiple cohorts, including the Global Neurodegeneration Proteomics Consortium.

Direct interactions between the human insula and hippocampus during memory encoding.

The hippocampus is critical for encoding episodic memories, but how it interacts with cortical regions during this process remains unclear. In this study, 16 participants with implanted electrodes in the insula (217 sites) and hippocampus (131 sites) viewed emotionally valenced words and attempted to recall them. During encoding, one subset of insular neuronal populations showed changes in aperiodic activity that predicted successful recall.

Top-down attention and Alzheimer's pathology affect cortical selectivity during learning, influencing episodic memory in older adults.

Effective memory formation declines in human aging. Diminished neural selectivity-reduced differential responses to preferred versus nonpreferred stimuli-may contribute to memory decline, but its drivers remain unclear. We investigated the effects of top-down attention and preclinical Alzheimer's disease (AD) pathology on neural selectivity in 166 cognitively unimpaired older participants using functional magnetic resonance imaging during a word-face/word-place associative memory task.

Medial temporal cortex supports object perception by integrating over visuospatial sequences.

Perception unfolds across multiple timescales. For humans and other primates, many object-centric visual attributes can be inferred 'at a glance' (i.e.

Parkinson's disease is characterized by vitamin B6-dependent inflammatory kynurenine pathway dysfunction.

Recent studies demonstrate that Parkinson's disease (PD) is associated with dysregulated metabolic flux through the kynurenine pathway (KP), in which tryptophan is converted to kynurenine (KYN), and KYN is subsequently metabolized to neuroactive compounds quinolinic acid (QA) and kynurenic acid (KA). Here, we used mass-spectrometry to compare blood and cerebral spinal fluid (CSF) KP metabolites between 158 unimpaired older adults and 177 participants with PD. We found increased neuroexcitatory QA/KA ratio in both plasma and CSF of PD participants associated with peripheral and cerebral inflammation and vitamin B deficiency.

Age-related differences in the relationship between sustained attention and associative memory and Memory-Guided inference.

Episodic memory enables the encoding and retrieval of novel associations, as well as the bridging across learned associations to draw novel inferences. A fundamental goal of memory science is to understand the factors that give rise to individual and age-related differences in memory-dependent cognition. Variability in episodic memory could arise, in part, from both individual differences in sustained attention and diminished attention in aging.

A 3'UTR Insertion Is a Candidate Causal Variant at the Locus Associated With Increased Risk for FTLD-TDP.

Background And Objectives: Single-nucleotide variants near associate with the risk of frontotemporal lobar dementia with TDP-43 inclusions (FTLD-TDP) and Alzheimer disease (AD) in genome-wide association studies (GWASs), but the causal variant at this locus remains unclear. Here, we asked whether a novel structural variant on is the causal variant.

Methods: An exploratory analysis identified structural variants on neurodegeneration-related genes.

Post-retrieval noradrenergic activation impairs subsequent memory depending on cortico-hippocampal reactivation.

When retrieved, seemingly stable memories can become sensitive to significant events, such as acute stress. The mechanisms underlying these memory dynamics remain poorly understood. Here, we show that noradrenergic stimulation after memory retrieval impairs subsequent remembering, depending on hippocampal and cortical signals emerging during retrieval.

Plasma Aβ/Aβ is sensitive to early cerebral amyloid accumulation and predicts risk of cognitive decline across the Alzheimer's disease spectrum.

Introduction: The availability of amyloid beta (Aβ) targeting therapies for Alzheimer's disease (AD) is increasing the demand for scalable biomarkers that are sensitive to early cerebral Aβ accumulation.

Methods: We evaluated fully-automated Lumipulse plasma Aβ/Aβ immunoassays for detecting cerebral Aβ in 457 clinically unimpaired (CU) and clinically impaired (CI) Stanford Alzheimer's Disease Research Center (Stanford ADRC) participants and 186 CU in the Stanford Aging and Memory Study (SAMS). Longitudinal change in ADRC plasma Aβ/Aβ and cognition and cross-sectional associations with SAMS memory and tau positron emission tomography (PET) were examined.

Top-down attention and Alzheimer's pathology impact cortical selectivity during learning, influencing episodic memory in older adults.

Human aging affects the ability to remember new experiences, in part, because of altered neural function during memory formation. One potential contributor to age-related memory decline is diminished neural selectivity -- i.e.

Cross-regional coordination of activity in the human brain during autobiographical self-referential processing.

For the human brain to operate, populations of neurons across anatomical structures must coordinate their activity within milliseconds. To date, our understanding of such interactions has remained limited. We recorded directly from the hippocampus (HPC), posteromedial cortex (PMC), ventromedial/orbital prefrontal cortex (OFC), and the anterior nuclei of the thalamus (ANT) during two experiments of autobiographical memory processing that are known from decades of neuroimaging work to coactivate these regions.

Post-retrieval stress impairs subsequent memory depending on hippocampal memory trace reinstatement during reactivation.

Upon retrieval, memories can become susceptible to meaningful events, such as stress. Post-retrieval memory changes may be attributed to an alteration of the original memory trace during reactivation-dependent reconsolidation or, alternatively, to the modification of retrieval-related memory traces that impact future remembering. Hence, how post-retrieval memory changes emerge in the human brain is unknown.

Comprehensive proteomics of CSF, plasma, and urine identify DDC and other biomarkers of early Parkinson's disease.

Parkinson's disease (PD) starts at the molecular and cellular level long before motor symptoms appear, yet there are no early-stage molecular biomarkers for diagnosis, prognosis prediction, or monitoring therapeutic response. This lack of biomarkers greatly impedes patient care and translational research-L-DOPA remains the standard of care more than 50 years after its introduction. Here, we performed a large-scale, multi-tissue, and multi-platform proteomics study to identify new biomarkers for early diagnosis and disease monitoring in PD.

Organ aging signatures in the plasma proteome track health and disease.

Animal studies show aging varies between individuals as well as between organs within an individual, but whether this is true in humans and its effect on age-related diseases is unknown. We utilized levels of human blood plasma proteins originating from specific organs to measure organ-specific aging differences in living individuals. Using machine learning models, we analysed aging in 11 major organs and estimated organ age reproducibly in five independent cohorts encompassing 5,676 adults across the human lifespan.

A 3'UTR Insertion Is a Candidate Causal Variant at the Locus Associated with Increased Risk for FTLD-TDP.

Background And Objectives: Single nucleotide variants near associate with risk of frontotemporal lobar dementia with TDP-43 inclusions (FTLD-TDP) and Alzheimer's disease (AD) in genome-wide association studies (GWAS), but the causal variant at this locus remains unclear. Here we asked whether a novel structural variant on is the causal variant.

Methods: An exploratory analysis identified structural variants on neurodegeneration-related genes.

Neural evidence for advantaged representation of first items in memory.

Visual areas activated during perception can retain specific information held in memory without the presence of physical stimuli via distributed activity patterns. Neuroimaging studies have shown that the delay-period representation of information in visual areas is modulated by factors such as memory load and task demands, raising the possibility of serial position as another potential modulator. Specifically, enhanced representation of first items during the post-encoding delay period may serve as a mechanism underlying the well-established but not well-understood primacy effect - the mnemonic advantage of first items.

Metrologically Traceable Quantification of 3 Apolipoprotein E Isoforms in Cerebrospinal Fluid.

Background: APOE genotype is associated with Alzheimer disease. Thus, the concentration of apolipoprotein E (apoE) isoforms in cerebrospinal fluid (CSF) could be altered in dementia. However, conflicting results have been obtained in different studies.

Representational integration and differentiation in the human hippocampus following goal-directed navigation.

As we learn, dynamic memory processes build structured knowledge across our experiences. Such knowledge enables the formation of internal models of the world that we use to plan, make decisions, and act. Recent theorizing posits that mnemonic mechanisms of differentiation and integration - which at one level may seem to be at odds - both contribute to the emergence of structured knowledge.

Cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment.

Cerebrospinal fluid (CSF) contains a tightly regulated immune system. However, knowledge is lacking about how CSF immunity is altered with aging or neurodegenerative disease. Here, we performed single-cell RNA sequencing on CSF from 45 cognitively normal subjects ranging from 54 to 82 years old.