Peripheral Blood Mononuclear Cell Mitochondrial Bioenergetics Is Impaired in De Novo Parkinson's Disease.

Mitochondrial dysfunction is increasingly recognized as a key driver of pathology in patients with Parkinson's disease (PD). Peripheral blood mononuclear cells (PBMCs) have emerged as an accessible way to characterize mitochondrial function in PD. The aim of this study was to conduct a preliminary evaluation of the clinical relevance of PBMC mitochondrial function as a biomarker in early PD.

Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies known and novel cross-population and ancestry-specific associations as novel risk loci for Alzheimer's disease.

Background: Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in ancestry groups of predominantly non-European ancestral background in genome-wide association studies (GWAS). We construct and analyze a multi-ancestry GWAS dataset in the Alzheimer's Disease Genetics Consortium (ADGC) to test for novel shared and population-specific late-onset Alzheimer's disease (LOAD) susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6728 African American, 8899 Hispanic (HIS), and 3232 East Asian individuals, performing within ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis.

Results: We identify 13 loci with cross-population associations including known loci at/near CR1, BIN1, TREM2, CD2AP, PTK2B, CLU, SHARPIN, MS4A6A, PICALM, ABCA7, APOE, and two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.

-klotho as a biomarker of amyloid levels in the cerebrospinal fluid.

Introduction: CSF -klotho levels might affect Aβ40, Aβ42, and the Aβ42/40 ratio in the cerebrospinal fluid (CSF).

Methods: CSF -klotho was assayed in ovariectomized rhesus macaques (NHPs) maintained on a Western-style diet (WSD) to assess the effect of estrogen hormone therapy (HT). CSF and serum -klotho was also analyzed in females and males of different ages and whether it was associated with Aβ42, Aβ40, or the Aβ42/40 ratio.

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.

improves cognitive function and alters the hippocampal metabolome of aged Tg2576 and wild-type mice.

Background: Alzheimer's disease (AD) is a growing public health problem in the aging population, with limited treatment options. We previously reported that herb water extract (CAW) attenuates cognitive decline in murine models of AD and aging.

Objective: To explore changes in the hippocampal metabolome associated with CAW's modulation of cognitive function and amyloid-β (Aβ) plaque load in aged Tg2576 and wild-type (WT) mice.

Oral Asiatic Acid Improves Cognitive Function and Modulates Antioxidant and Mitochondrial Pathways in Female 5xFAD Mice.

Extracts of the plant can enhance mitochondrial function, promote antioxidant activity and improve cognitive deficits. Asiatic acid (AA) is one of the constituent triterpene compounds present in the plant. In this study, we explore the effects of AA on brain mitochondrial function, antioxidant response and cognition in a beta-amyloid (Aβ)-overexpressing 5xFAD mouse line.

The CD74 inhibitor DRhQ improves short-term memory and mitochondrial function in 5xFAD mouse model of Aβ accumulation.

Neuroinflammation and mitochondrial dysfunction are early events in Alzheimer's disease (AD) and contribute to neurodegeneration and cognitive impairment. Evidence suggests that the inflammatory axis mediated by macrophage migration inhibitory factor (MIF) binding to its receptor, CD74, plays an important role in many central nervous system (CNS) disorders such as AD. Our group has developed DRhQ, a novel CD74 binding construct which competitively inhibits MIF binding, blocks macrophage activation and migration into the CNS, enhances anti-inflammatory microglia cell numbers and reduces pro-inflammatory gene expression.

Sex Differences in Basal Cortisol Levels Across Body Fluid Compartments in a Cross-sectional Study of Healthy Adults.

Context: Many studies have moved toward saliva and peripheral blood sampling for studying cortisol, even in relation to disorders of the brain. However, the degree to which peripheral cortisol reflects central cortisol levels has yet to be comprehensively described. Data describing the effect that biological characteristics such as age and sex have on cortisol levels across compartments is also limited.

ω-3 PUFA for Secondary Prevention of White Matter Lesions and Neuronal Integrity Breakdown in Older Adults: A Randomized Clinical Trial.

Importance: Older adults with lower intake and tissue levels of long-chain ω-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA; 20:5) and docosahexaenoic acid (DHA; 22:6) have more brain white matter lesions (WMLs), an association suggesting that small-vessel ischemic disease, a major contributor to the development of dementia, including Alzheimer disease, may be preventable through ω-3 treatment.

Objective: To determine whether ω-3 treatment reduces WML accumulation in older adults without dementia harboring WMLs and with suboptimal ω-3 status.

Design, Setting, And Participants: This quadruple-blinded, placebo-controlled, randomized clinical trial with treatment stratification by apolipoprotein E ε4 allele (APOE*E4) carrier status used linear mixed-effects models to estimate mean annual change between groups.

The Time Course of Changes in Prefrontal Cortex Activity During Walking in People With Parkinson's Disease.

Background: Walking abnormalities in people with Parkinson's disease (PD) are characterized by a shift in locomotor control from healthy automaticity to compensatory, executive control, mainly located in the prefrontal cortex (PFC). Although PFC activity during walking increases in people with PD, the time course of PFC activity during walking and its relationship to clinical or gait characteristics is unknown.

Objective: To identify the time course of PFC activity during walking in people with PD.

Parkinson's disease variant detection and disclosure: PD GENEration, a North American study.

Variants in seven genes (LRRK2, GBA1, PRKN, SNCA, PINK1, PARK7 and VPS35) have been formally adjudicated as causal contributors to Parkinson's disease; however, individuals with Parkinson's disease are often unaware of their genetic status since clinical testing is infrequently offered. As a result, genetic information is not incorporated into clinical care, and variant-targeted precision medicine trials struggle to enrol people with Parkinson's disease. Understanding the yield of genetic testing using an established gene panel in a large, geographically diverse North American population would help patients, clinicians, clinical researchers, laboratories and insurers better understand the importance of genetics in approaching Parkinson's disease.

Amelioration of age-related cognitive decline and anxiety in mice by extract varies by sex, dose and mode of administration.

A water extract (CAW) of the Ayurvedic plant administered in drinking water has been shown to improve cognitive deficits in mouse models of aging and neurodegenerative diseases. Here the effects of CAW administered in drinking water or the diet on cognition, measures of anxiety and depression-like behavior in healthy aged mice are compared. Three- and eighteen-month-old male and female C57BL6 mice were administered rodent AIN-93M diet containing CAW (0, 0.

Mode of administration influences plasma levels of active compounds in 5xFAD mice while markers of neuroinflammation remain unaltered.

Introduction: A water extract of (L.) Urban [Apiaceae] (CAW) has demonstrated cognitive-enhancing effects in mouse models of Alzheimer's disease and aging, the magnitude of which is influenced by whether CAW is delivered in the drinking water or the diet. These cognitive benefits are accompanied by improvements in oxidative stress and mitochondrial function in the brain, two pathways related to the neuroinflammatory response.

Integrating High-Resolution Mass Spectral Data, Bioassays and Computational Models to Annotate Bioactives in Botanical Extracts: Case Study Analysis of Extract Associates Dicaffeoylquinic Acids with Protection against Amyloid-β Toxicity.

Rapid screening of botanical extracts for the discovery of bioactive natural products was performed using a fractionation approach in conjunction with flow-injection high-resolution mass spectrometry for obtaining chemical fingerprints of each fraction, enabling the correlation of the relative abundance of molecular features (representing individual phytochemicals) with the read-outs of bioassays. We applied this strategy for discovering and identifying constituents of () that protect against Aβ cytotoxicity in vitro. has been associated with improving mental health and cognitive function, with potential use in Alzheimer's disease.

Amelioration of age-related cognitive decline and anxiety in mice by extract varies by sex, dose and mode of administration.

We have previously reported that a water extract (CAW) of the Ayurvedic plant administered in drinking water can improve cognitive deficits in mouse models of aging and neurodegenerative diseases. Here we compared the effects of CAW administered in drinking water or the diet on cognition, measures of anxiety and depression-like behavior in healthy aged mice. Three- and eighteen-month-old male and female C57BL6 mice were administered rodent AIN-93M diet containing CAW (0, 0.

Analysis of the longitudinal stability of human plasma miRNAs and implications for disease biomarkers.

There is great interest in developing clinical biomarker assays that can aid in non-invasive diagnosis and/or monitoring of human diseases, such as cancer, cardiovascular disease, and neurological diseases. Yet little is known about the longitudinal stability of miRNAs in human plasma. Here we assessed the intraindividual longitudinal stability of miRNAs in plasma from healthy human adults, and the impact of common factors (e.

Recommendations for reproducibility of cerebrospinal fluid extracellular vesicle studies.

Cerebrospinal fluid (CSF) is a clear, transparent fluid derived from blood plasma that protects the brain and spinal cord against mechanical shock, provides buoyancy, clears metabolic waste and transports extracellular components to remote sites in the brain. Given its contact with the brain and the spinal cord, CSF is the most informative biofluid for studies of the central nervous system (CNS). In addition to other components, CSF contains extracellular vesicles (EVs) that carry bioactive cargoes (e.

Bioanalytical method validation and application to a phase 1, double-blind, randomized pharmacokinetic trial of a standardized (L.) Urban water extract product in healthy older adults.

is an herbaceous plant reputed in Eastern medicine to improve memory. Preclinical studies have shown that aqueous extract (CAW) improves neuronal health, reduces oxidative stress, and positively impacts learning and cognition. This study aimed to develop and validate bioanalytical methods for detecting known bioactive compounds from in human biological matrices and apply them to a human pharmacokinetic trial in healthy older adults.

Human cerebrospinal fluid contains diverse lipoprotein subspecies enriched in proteins implicated in central nervous system health.

Lipoproteins in cerebrospinal fluid (CSF) of the central nervous system (CNS) resemble plasma high-density lipoproteins (HDLs), which are a compositionally and structurally diverse spectrum of nanoparticles with pleiotropic functionality. Whether CSF lipoproteins (CSF-Lps) exhibit similar heterogeneity is poorly understood because they are present at 100-fold lower concentrations than plasma HDL. To investigate the diversity of CSF-Lps, we developed a sensitive fluorescent technology to characterize lipoprotein subspecies in small volumes of human CSF.

Lifelong Association of Disorders Related to Military Trauma with Subsequent Parkinson's Disease.

Background: Trauma-related disorders such as traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) are emerging as risk factors for Parkinson's disease (PD), but their association with development of PD and independence from comorbid disorders remains unknown.

Objective: To examine TBI and PTSD related to early trauma in military veterans using a case-control study.

Methods: PD was identified by International Classification of Diseases (ICD) code, recurrent PD-specific prescriptions, and availability of 5+ years of earlier records.

Screening and Targeting Risk Factors for Prodromal Synucleinopathy: Taking Steps toward a Prescriptive Multi-modal Framework.

As the prevalence of Parkinson's disease (PD) grows, so too does the population at-risk of developing PD, those in the so-called prodromal period. This period can span from those experiencing subtle motor deficits yet not meeting full diagnostic criteria or those with physiologic markers of disease alone. Several disease-modifying therapies have failed to show a neuroprotective effect.

Gait and balance in apolipoprotein Ɛ4 allele carriers in older adults and Parkinson's disease.

Background: Gait and balance impairments are among the most troublesome and heterogeneous in Parkinson's disease (PD). This heterogeneity may, in part, reflect genetic variation. The apolipoprotein E () gene has three major allelic variants (ε2, ε3 and ε4).

Listening session with the US Food and Drug Administration, Lewy Body Dementia Association, and an expert panel.

Unlabelled: The regulatory path for drug approval is increasingly well defined. Drugs for the treatment of Alzheimer disease (AD) need to show statistically significant benefit over placebo with respect to cognitive and functional measures, with the Clinical Dementia Rating scale and Alzheimer's Disease Assessment Scale-Cognitive Subscale being among the most often used instruments in AD clinical trials. In contrast, there are no validated instruments for use in clinical trials of drugs for the treatment of dementia with Lewy bodies.