Publications by authors named "Mitchel A Kling"

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects over 1% of population over age 60. It is defined by motor and nonmotor symptoms including a spectrum of cognitive impairments known as Parkinson's disease dementia (PDD). Currently, the only US Food and Drug Administration-approved treatment for PDD is rivastigmine, which inhibits acetylcholinesterase and butyrylcholinesterase increasing the level of acetylcholine in the brain.

View Article and Find Full Text PDF

Introduction: A rapid and reliable neuropsychological protocol is essential for the efficient assessment of neurocognitive constructs related to emergent neurodegenerative diseases. We developed an AI-assisted, digitally administered/scored neuropsychological protocol that can be remotely administered in ~10 min. This protocol assesses the requisite neurocognitive constructs associated with emergent neurodegenerative illnesses.

View Article and Find Full Text PDF

Background: Alzheimer's disease (AD) shares risk factors with cardiovascular disease (CVD) and dysregulated cholesterol metabolism is a mechanism common to both diseases. Cholesterol efflux capacity (CEC) is an ex vivo metric of plasma high-density lipoprotein (HDL) function and inversely predicts incident CVD independently of other risk factors. Cholesterol pools in the central nervous system (CNS) are largely separate from those in blood, and CNS cholesterol excess may promote neurodegeneration.

View Article and Find Full Text PDF

Study Objectives: Self-reported sleep disturbance has been established as a risk factor and predictor for posttraumatic stress disorder (PTSD); however, less is known about the relationship between objective sleep and PTSD symptom clusters, and the specific role of hyperarousal. The present study examined the relationships between sleep continuity and architecture on PTSD symptom clusters.

Methods: Participants underwent two in-laboratory sleep studies to assess sleep continuity and architecture.

View Article and Find Full Text PDF

Plasmalogens are a specific type of glycerophospholipid found in especially high levels in neuronal membranes. Decreased blood and brain levels of docosahexaenoic acid (DHA) containing plasmalogens are associated with decreased cognition and neuromuscular function in humans. Administration of 1-O-alkyl-2-acylglycerol (AAG) plasmalogen precursors containing DHA at the sn-2 position dose-dependently increase blood DHA plasmalogens and are neuroprotective in animal models of neurodegeneration at doses between 10 and 50 mg/kg.

View Article and Find Full Text PDF

Introduction: Altered lipid metabolism is implicated in Alzheimer's disease (AD), but the mechanisms remain obscure. Aging-related declines in circulating plasmalogens containing omega-3 fatty acids may increase AD risk by reducing plasmalogen availability.

Methods: We measured four ethanolamine plasmalogens (PlsEtns) and four closely related phosphatidylethanolamines (PtdEtns) from the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 1547 serum) and University of Pennsylvania (UPenn; n = 112 plasma) cohorts, and derived indices reflecting PlsEtn and PtdEtn metabolism: PL-PX (PlsEtns), PL/PE (PlsEtn/PtdEtn ratios), and PBV (plasmalogen biosynthesis value; a composite index).

View Article and Find Full Text PDF

Background: Basic research has implicated intracellular cholesterol in neurons, microglia, and astrocytes in the pathogenesis of Alzheimer's disease (AD), but there is presently no assay to access intracellular cholesterol in neural cells in living people in the context of AD.

Objective: To devise and characterize an assay that can access intracellular cholesterol and cholesterol efflux in neural cells in living subjects.

Methods: We modified the protocol for high-density lipoprotein cholesterol efflux capacity (CEC) from macrophages, a biomarker that accesses cholesterol in macrophages in atherosclerosis.

View Article and Find Full Text PDF

Introduction: Increasing evidence suggests a role for the gut microbiome in central nervous system disorders and a specific role for the gut-brain axis in neurodegeneration. Bile acids (BAs), products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria. They have major regulatory and signaling functions and seem dysregulated in Alzheimer's disease (AD).

View Article and Find Full Text PDF

Introduction: The dynamic range of cerebrospinal fluid (CSF) amyloid β (Aβ) measurement does not parallel to cognitive changes in Alzheimer's disease (AD) and cognitively normal (CN) subjects across different studies. Therefore, identifying novel proteins to characterize symptomatic AD samples is important.

Methods: Proteins were profiled using a multianalyte platform by Rules Based Medicine (MAP-RBM).

View Article and Find Full Text PDF

Plasma homocysteine, a metabolite involved in key cellular methylation processes seems to be implicated in cognitive functions and cardiovascular health with its high levels representing a potential modifiable risk factor for Alzheimer's disease (AD) and other dementias. A better understanding of the genetic factors regulating homocysteine levels, particularly in non-white populations, may help in risk stratification analyses of existing clinical trials and may point to novel targets for homocysteine-lowering therapy. To identify genetic influences on plasma homocysteine levels in individuals with African ancestry, we performed a targeted gene and pathway-based analysis using a priori biological information and then to identify new association performed a genome-wide association study.

View Article and Find Full Text PDF

Objective: To determine whether subjective memory complaints (SMCs) are associated with performance on objective cognitive measures and psychological factors in healthy, community-dwelling older adults.

Method: The cohort was composed of adults, 65 years and older with no clinical evidence of cognitive impairment (n = 125). Participants were administered: CogState computerized neurocognitive battery, Prospective Retrospective Memory Questionnaire, personality and meaning-in-life measures.

View Article and Find Full Text PDF

Background: A critical and as-yet unmet need in Alzheimer disease (AD) research is the development of novel markers that can identify individuals at risk for cognitive decline due to AD. This would aid intervention trials designed to slow the progression of AD by increasing diagnostic certainty, and provide new pathophysiologic clues and potential drug targets.

Results: We used two metabolomics platforms (gas chromatography-time of flight mass spectrometry [GC-TOF] and liquid chromatography LC-ECA array [LC-ECA]) to measure a number of metabolites in cerebrospinal fluid (CSF) from patients with AD dementia and from cognitively normal controls.

View Article and Find Full Text PDF

C-reactive protein (CRP) participates in the systemic response to inflammation. Previous studies report inconsistent findings regarding the relationship between plasma CRP and Alzheimer's disease (AD). We measured plasma CRP in 203 subjects with AD, 58 subjects with mild cognitive impairment (MCI) and 117 normal aging subjects and administered annual Mini-Mental State Examinations (MMSE) during a 3-year follow-up period to investigate CRP's relationship with diagnosis and progression of cognitive decline.

View Article and Find Full Text PDF

Objective: Patients with alcohol dependence presenting for treatment may have multiple associated co-morbid conditions and limited social supports, which complicate treatment. Each of these factors has been independently associated with complaints of insomnia. In this preliminary study, we investigated the relations between insomnia complaints and socio-demographic factors and psychiatric co-morbidity in treatment-seeking patients with alcohol dependence.

View Article and Find Full Text PDF

A growing body of evidence demonstrates an association between vascular risk factors and Alzheimer's disease. This study investigated the frequency and severity of atherosclerotic plaques in the circle of Willis in Alzheimer's disease and multiple other neurodegenerative diseases. Semi-quantitative data from gross and microscopic neuropathological examinations in 1000 cases were analysed, including 410 with a primary diagnosis of Alzheimer's disease, 230 with synucleinopathies, 157 with TDP-43 proteinopathies, 144 with tauopathies and 59 with normal ageing.

View Article and Find Full Text PDF

Vascular disease was once considered the principal cause of aging-related dementia. More recently, however, research emphasis has shifted to studies of progressive neurodegenerative disease processes, such as those giving rise to neuritic plaques, neurofibrillary tangles, and Lewy bodies. Although these studies have led to critical insights and potential therapeutic strategies, interest in the role of systemic and cerebrovascular disease mechanisms waned and has received relatively less attention and research support.

View Article and Find Full Text PDF

Patents with major depression have evidence of a proinflammatory state with consistent elevations in acute phase proteins and in the levels of inflammatory mediators such as interleukin-6 and tumor necrosis factor-α. We report here a study of the serum levels of immunoglobulin A (IgA) in medication-free patients with major depression in the remitted state (ruMDD). Selective IgA deficiency is the most common form of immunoglobulin abnormality, and is often associated with a higher than expected incidence of proinflammatory and autoimmune phenomena.

View Article and Find Full Text PDF

Background: The debilitating effects of chronic glucocorticoids excess are well-known, but comparatively little is understood about the role of acute cortisol. Indirect evidence in rodents suggests that acute cortisone could selectively increase some forms of long-duration aversive states, such as "anxiety," but not relatively similar, briefer aversive states, such as "fear." However, no prior experimental studies in humans consider the unique effects of cortisol on anxiety and fear, using well-validated methods for eliciting these two similar but dissociable aversive states.

View Article and Find Full Text PDF

Background: Major depressive disorder affects a substantial percentage of the U.S. population, and can be highly debilitating.

View Article and Find Full Text PDF

Background: Evidence is accumulating that mitochondrial dysfunction is involved in the pathophysiology of bipolar disorder and schizophrenia. Cerebrospinal fluid (CSF) concentration of lactate, a product of extra-mitochondrial glucose metabolism, is commonly elevated in individuals with mitochondrial disorders, especially those with neuropsychiatric symptoms. We tested the hypothesis that patients with bipolar disorder and schizophrenia would, on average, have elevated CSF lactate concentrations compared with healthy control subjects.

View Article and Find Full Text PDF

In contrast to relapse, the mechanisms of multiple sclerosis (MS) disease progression are less understood and appear not to be exclusively inflammatory in nature. In this pilot study we investigated the relationship between disturbed CNS energy metabolism and MS disease progression. We tested the hypothesis that cerebrospinal fluid (CSF) concentrations of sorbitol, fructose, and lactate, all metabolites of extra-mitochondrial glucose metabolism, would be elevated in secondary progressive (SP) MS patients and would be associated with worsening neurologic disability.

View Article and Find Full Text PDF

Context: Both highly stress-reactive and novelty-seeking individuals are susceptible to alcohol use disorders. Variation in stress reactivity, exploration, and response to novelty have been attributed to differences in corticotropin-releasing hormone (CRH) system function. As such, CRH gene variation may influence risk for alcohol use and dependence.

View Article and Find Full Text PDF

Recent preclinical and clinical research has demonstrated that the neuropeptide substance P (SP) plays a role in the central nervous system (CNS) response to stress, and perhaps in the etiology of major depression and/or anxiety disorders. The nature of this role, however, is poorly understood. A limited body of evidence suggests that in medication-free depressed patients, cerebrospinal fluid (CSF) concentrations of SP may be elevated relative to healthy controls.

View Article and Find Full Text PDF

Background: Stress is an important factor in the development and maintenance of anxiety disorders. Stress also potentiates anxiety-like response in animals, but empirical evidence for a similar effect in humans is still lacking.

Methods: To test whether stress increases anxiety in humans, we examined the ability of a social stressor (speech and a counting task) to potentiate the facilitation of startle in the dark.

View Article and Find Full Text PDF