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Breakthroughs in Diagnostic Prediction and Fundamental Therapeutics of Dementia and Movement Disorders

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (25 March 2024) | Viewed by 25285

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Dr. Ichiro Kawahata

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Department of CNS Drug Innovation, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan
Interests: CaMKII; neuropsychiatry disorders; drug addiction; neuroinflammation; dementia
Special Issues, Collections and Topics in MDPI journals

Dr. Yasemin M. Akay

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Department of Biomedical Engineering, University of Houston, Houston, TX 77204-5060, USA
Interests: coronary artery disease; stent; noninvasive monitoring; nonlinear dynamics analysis; approximate entropy; 3D co-culture; glioblastoma; astrocytes; tumor microenvironment; PEGDA; addiction; cancer research; data science in medicine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The increase in patients with dementia and motor dysfunction due to the global aging population is a significant social problem. No fundamental treatment for these cognitive-motor disorders has yet been developed. Therefore, understanding the etiology of aging-related disorders and exploring unique therapeutic targets to develop total therapies are urgent issues. Accordingly, comprehending the degeneration of brain function with aging is essential. To this end, it is necessary to distinguish the molecular mechanisms required to maintain neuronal homeostasis and the characteristics of pathogenic proteins. Thus, this Special Issue focuses on the pathogenic mechanism involved in the etiology of neurodegeneration, which includes Alzheimer’s disease (AD), Parkinson’s (PD), and dementia with Lewy bodies (DLB), demonstrating the physiological significance of the pathogenic proteins. We also focus on the disease-related biomarkers associated with the age- and disease-induced loss of neuronal homeostasis. The goal of this Special Issue is to subsequently improve our understanding of aging-related neurodegenerative disorders and to make breakthroughs in the prediction of pathogenesis and the development of fundamental treatments for these diseases.

Potential topics include, but are not limited to: Parkinson’s disease (PD), Dementia with Lewy bodies (DLB), Alzheimer’s disease (AD), pathogenic proteins in the above diseases, biomarkers for AD, PD, and DLB, therapeutic targets and drugs for AD, PD, and DLB, and reviews and future perspectives on the above topics.

Dr. Ichiro Kawahata
Dr. Yasemin M. Akay
Guest Editors

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Keywords

Parkinson’s disease
dementia with Lewy bodies
Alzheimer’s disease
pathogenic protein
biomarker
therapeutic target
drug

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Breakthroughs in Diagnostic Prediction and Fundamental Therapeutics of Dementia and Movement Disorders, 2nd Edition in International Journal of Molecular Sciences (3 articles)

Published Papers (8 papers)

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Research

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19 pages, 6452 KiB

Open AccessArticle

[¹⁸F]Flotaza for Aβ Plaque Diagnostic Imaging: Evaluation in Postmortem Human Alzheimer’s Disease Brain Hippocampus and PET/CT Imaging in 5xFAD Transgenic Mice

by Yasmin K. Sandhu, Harman S. Bath, Jasmine Shergill, Christopher Liang, Amina U. Syed, Allyson Ngo, Fariha Karim, Geidy E. Serrano, Thomas G. Beach and Jogeshwar Mukherjee

Int. J. Mol. Sci. 2024, 25(14), 7890; https://doi.org/10.3390/ijms25147890 - 18 Jul 2024

Cited by 6 | Viewed by 1476

Abstract

The diagnostic value of imaging Aβ plaques in Alzheimer’s disease (AD) has accelerated the development of fluorine-18 labeled radiotracers with a longer half-life for easier translation to clinical use. We have developed [¹⁸F]flotaza, which shows high binding to Aβ plaques in postmortem human AD brain slices with low white matter binding. We report the binding of [¹⁸F]flotaza in postmortem AD hippocampus compared to cognitively normal (CN) brains and the evaluation of [¹⁸F]flotaza in transgenic 5xFAD mice expressing Aβ plaques. [¹⁸F]Flotaza binding was assessed in well-characterized human postmortem brain tissue sections consisting of HP CA1-subiculum (HP CA1-SUB) regions in AD (n = 28; 13 male and 15 female) and CN subjects (n = 32; 16 male and 16 female). Adjacent slices were immunostained with anti-Aβ and analyzed using QuPath. In vitro and in vivo [¹⁸F]flotaza PET/CT studies were carried out in 5xFAD mice. Post-mortem human brain slices from all AD subjects were positively IHC stained with anti-Aβ. High [¹⁸F]flotaza binding was measured in the HP CA1-SUB grey matter (GM) regions compared to white matter (WM) of AD subjects with GM/WM > 100 in some subjects. The majority of CN subjects had no decipherable binding. Male AD exhibited greater WM than AD females (AD WM♂/WM♀ > 5; p < 0.001) but no difference amongst CN WM. In vitro studies in 5xFAD mice brain slices exhibited high binding [¹⁸F]flotaza ratios (>50 versus cerebellum) in the cortex, HP, and thalamus. In vivo, PET [¹⁸F]flotaza exhibited binding to Aβ plaques in 5xFAD mice with SUVR~1.4. [¹⁸F]Flotaza is a new Aβ plaque PET imaging agent that exhibited high binding to Aβ plaques in postmortem human AD. Along with the promising results in 5xFAD mice, the translation of [¹⁸F]flotaza to human PET studies may be worthwhile. Full article

(This article belongs to the Special Issue Breakthroughs in Diagnostic Prediction and Fundamental Therapeutics of Dementia and Movement Disorders)

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23 pages, 4288 KiB

Open AccessArticle

High-Yield α-Synuclein Purification and Ionic Strength Modification Pivotal to Seed Amplification Assay Performance and Reproducibility

by Chelva Janarthanam, Griffin Clabaugh, Zerui Wang, Bradley R. Melvin, Ileia Scheibe, Huajun Jin, Vellareddy Anantharam, Ramona J. B. Urbauer, Jeffrey L. Urbauer, Jiyan Ma, Arthi Kanthasamy, Xuemei Huang, Vincenzo Donadio, Wenquan Zou and Anumantha G. Kanthasamy

Int. J. Mol. Sci. 2024, 25(11), 5988; https://doi.org/10.3390/ijms25115988 - 30 May 2024

Cited by 1 | Viewed by 2685

Abstract

Alpha-synuclein seed amplification assays (αSyn-SAAs) have emerged as promising diagnostic tools for Parkinson’s disease (PD) by detecting misfolded αSyn and amplifying the signal through cyclic shaking and resting in vitro. Recently, our group and others have shown that multiple biospecimens, including CSF, skin, and submandibular glands (SMGs), can be used to seed the aggregation reaction and robustly distinguish between patients with PD and non-disease controls. The ultrasensitivity of the assay affords the ability to detect minute quantities of αSyn in peripheral tissues, but it also produces various technical challenges of variability. To address the problem of variability, we present a high-yield αSyn protein purification protocol for the efficient production of monomers with a low propensity for self-aggregation. We expressed wild-type αSyn in BL21 Escherichia coli, lysed the cells using osmotic shock, and isolated αSyn using acid precipitation and fast protein liquid chromatography (FPLC). Following purification, we optimized the ionic strength of the reaction buffer to distinguish the fluorescence maximum (Fmax) separation between disease and healthy control tissues for enhanced assay performance. Our protein purification protocol yielded high quantities of αSyn (average: 68.7 mg/mL per 1 L of culture) and showed highly precise and robust αSyn-SAA results using brain, skin, and SMGs with inter-lab validation. Full article

(This article belongs to the Special Issue Breakthroughs in Diagnostic Prediction and Fundamental Therapeutics of Dementia and Movement Disorders)

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21 pages, 4980 KiB

Open AccessArticle

Melatonin Inhibits Hypoxia-Induced Alzheimer’s Disease Pathogenesis by Regulating the Amyloidogenic Pathway in Human Neuroblastoma Cells

by Nongnuch Singrang, Chutikorn Nopparat, Jiraporn Panmanee and Piyarat Govitrapong

Int. J. Mol. Sci. 2024, 25(10), 5225; https://doi.org/10.3390/ijms25105225 - 10 May 2024

Cited by 3 | Viewed by 2247

Abstract

Stroke and Alzheimer’s disease (AD) are prevalent age-related diseases; however, the relationship between these two diseases remains unclear. In this study, we aimed to investigate the ability of melatonin, a hormone produced by the pineal gland, to alleviate the effects of ischemic stroke leading to AD by observing the pathogenesis of AD hallmarks. We utilized SH-SY5Y cells under the conditions of oxygen–glucose deprivation (OGD) and oxygen-glucose deprivation and reoxygenation (OGD/R) to establish ischemic stroke conditions. We detected that hypoxia-inducible factor-1α (HIF-1α), an indicator of ischemic stroke, was highly upregulated at both the protein and mRNA levels under OGD conditions. Melatonin significantly downregulated both HIF-1α mRNA and protein expression under OGD/R conditions. We detected the upregulation of β-site APP-cleaving enzyme 1 (BACE1) mRNA and protein expression under both OGD and OGD/R conditions, while 10 µM of melatonin attenuated these effects and inhibited beta amyloid (Aβ) production. Furthermore, we demonstrated that OGD/R conditions were able to activate the BACE1 promoter, while melatonin inhibited this effect. The present results indicate that melatonin has a significant impact on preventing the aberrant development of ischemic stroke, which can lead to the development of AD, providing new insight into the prevention of AD and potential stroke treatments. Full article

(This article belongs to the Special Issue Breakthroughs in Diagnostic Prediction and Fundamental Therapeutics of Dementia and Movement Disorders)

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21 pages, 5118 KiB

Open AccessArticle

Difference of Cerebrospinal Fluid Biomarkers and Neuropsychiatric Symptoms Profiles among Normal Cognition, Mild Cognitive Impairment, and Dementia Patient

by Ching-Chi Hsu, Shiow-Ing Wang, Hong-Chun Lin, Eric S. Lin, Fan-Pei Yang, Ching-Mao Chang and James Cheng-Chung Wei

Int. J. Mol. Sci. 2024, 25(7), 3919; https://doi.org/10.3390/ijms25073919 - 31 Mar 2024

Cited by 1 | Viewed by 5852

Abstract

The delineation of biomarkers and neuropsychiatric symptoms across normal cognition, mild cognitive impairment (MCI), and dementia stages holds significant promise for early diagnosis and intervention strategies. This research investigates the association of neuropsychiatric symptoms, evaluated via the Neuropsychiatric Inventory (NPI), with cerebrospinal fluid (CSF) biomarkers (Amyloid-β42, P-tau, T-tau) across a spectrum of cognitive states to enhance diagnostic accuracy and treatment approaches. Drawing from the National Alzheimer’s Coordinating Center’s Uniform Data Set Version 3, comprising 977 individuals with normal cognition, 270 with MCI, and 649 with dementia. To assess neuropsychiatric symptoms, we employed the NPI to understand the behavioral and psychological symptoms associated with each cognitive category. For the analysis of CSF biomarkers, we measured levels of Amyloid-β42, P-tau, and T-tau using the enzyme-linked immunosorbent assay (ELISA) and Luminex multiplex xMAP assay protocols. These biomarkers are critical in understanding the pathophysiological underpinnings of Alzheimer’s disease and its progression, with specific patterns indicative of disease stage and severity. This study cohort consists of 1896 participants, which is composed of 977 individuals with normal cognition, 270 with MCI, and 649 with dementia. Dementia is characterized by significantly higher NPI scores, which are largely reflective of mood-related symptoms (p < 0.001). In terms of biomarkers, normal cognition shows median Amyloid-β at 656.0 pg/mL, MCI at 300.6 pg/mL, and dementia at 298.8 pg/mL (p < 0.001). Median P-tau levels are 36.00 pg/mL in normal cognition, 49.12 pg/mL in MCI, and 58.29 pg/mL in dementia (p < 0.001). Median T-tau levels are 241.0 pg/mL in normal cognition, 140.6 pg/mL in MCI, and 298.3 pg/mL in dementia (p < 0.001). Furthermore, the T-tau/Aβ-42 ratio increases progressively from 0.058 in the normal cognition group to 0.144 in the MCI group, and to 0.209 in the dementia group (p < 0.001). Similarly, the P-tau/Aβ-42 ratio also escalates from 0.305 in individuals with normal cognition to 0.560 in MCI, and to 0.941 in dementia (p < 0.001). The notable disparities in NPI and CSF biomarkers among normal, MCI and Alzheimer’s patients underscore their diagnostic potential. Their combined assessment could greatly improve early detection and precise diagnosis of MCI and dementia, facilitating more effective and timely treatment strategies. Full article

(This article belongs to the Special Issue Breakthroughs in Diagnostic Prediction and Fundamental Therapeutics of Dementia and Movement Disorders)

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12 pages, 3539 KiB

Open AccessArticle

Using Fatty Acid-Binding Proteins as Potential Biomarkers to Discriminate between Parkinson’s Disease and Dementia with Lewy Bodies: Exploration of a Novel Technique

by Ichiro Kawahata, Tomoki Sekimori, Hideki Oizumi, Atsushi Takeda and Kohji Fukunaga

Int. J. Mol. Sci. 2023, 24(17), 13267; https://doi.org/10.3390/ijms241713267 - 26 Aug 2023

Cited by 9 | Viewed by 3461

Abstract

An increase in the global aging population is leading to an increase in age-related conditions such as dementia and movement disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and dementia with Lewy bodies (DLB). The accurate prediction of risk factors associated with these disorders is crucial for early diagnosis and prevention. Biomarkers play a significant role in diagnosing and monitoring diseases. In neurodegenerative disorders like α-synucleinopathies, specific biomarkers can indicate the presence and progression of disease. We previously demonstrated the pathogenic impact of fatty acid-binding proteins (FABPs) in α-synucleinopathies. Therefore, this study investigated FABPs as potential biomarkers for Lewy body diseases. Plasma FABP levels were measured in patients with AD, PD, DLB, and mild cognitive impairment (MCI) and healthy controls. Plasma FABP3 was increased in all groups, while the levels of FABP5 and FABP7 tended to decrease in the AD group. Additionally, FABP2 levels were elevated in PD. A correlation analysis showed that higher FABP3 levels were associated with decreased cognitive function. The plasma concentrations of Tau, GFAP, NF-L, and UCHL1 correlated with cognitive decline. A scoring method was applied to discriminate between diseases, demonstrating high accuracy in distinguishing MCI vs. CN, AD vs. DLB, PD vs. DLB, and AD vs. PD. The study suggests that FABPs could serve as potential biomarkers for Lewy body diseases and aid in early disease detection and differentiation. Full article

(This article belongs to the Special Issue Breakthroughs in Diagnostic Prediction and Fundamental Therapeutics of Dementia and Movement Disorders)

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Review

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13 pages, 533 KiB

Open AccessReview

Therapeutic Application of Modulators of Endogenous Cannabinoid System in Parkinson’s Disease

by Leonid G. Khaspekov and Sergey N. Illarioshkin

Int. J. Mol. Sci. 2024, 25(15), 8520; https://doi.org/10.3390/ijms25158520 - 5 Aug 2024

Cited by 1 | Viewed by 2055

Abstract

The endogenous cannabinoid system (ECS) of the brain plays an important role in the molecular pathogenesis of Parkinson’s disease (PD). It is involved in the formation of numerous clinical manifestations of the disease by regulating the level of endogenous cannabinoids and changing the activation of cannabinoid receptors (CBRs). Therefore, ECS modulation with new drugs specifically designed for this purpose may be a promising strategy in the treatment of PD. However, fine regulation of the ECS is quite a complex task due to the functional diversity of CBRs in the basal ganglia and other parts of the central nervous system. In this review, the effects of ECS modulators in various experimental models of PD in vivo and in vitro, as well as in patients with PD, are analyzed. Prospects for the development of new cannabinoid drugs for the treatment of motor and non-motor symptoms in PD are presented. Full article

(This article belongs to the Special Issue Breakthroughs in Diagnostic Prediction and Fundamental Therapeutics of Dementia and Movement Disorders)

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21 pages, 5219 KiB

Open AccessReview

Alzheimer’s Amyloid Hypothesis and Antibody Therapy: Melting Glaciers?

by Poul F. Høilund-Carlsen, Abass Alavi, Rudolph J. Castellani, Rachael L. Neve, George Perry, Mona-Elisabeth Revheim and Jorge R. Barrio

Int. J. Mol. Sci. 2024, 25(7), 3892; https://doi.org/10.3390/ijms25073892 - 31 Mar 2024

Cited by 13 | Viewed by 4240

Abstract

The amyloid cascade hypothesis for Alzheimer’s disease is still alive, although heavily challenged. Effective anti-amyloid immunotherapy would confirm the hypothesis’ claim that the protein amyloid-beta is the cause of the disease. Two antibodies, aducanumab and lecanemab, have been approved by the U.S. Food and Drug Administration, while a third, donanemab, is under review. The main argument for the FDA approvals is a presumed therapy-induced removal of cerebral amyloid deposits. Lecanemab and donanemab are also thought to cause some statistical delay in the determination of cognitive decline. However, clinical efficacy that is less than with conventional treatment, selection of amyloid-positive trial patients with non-specific amyloid-PET imaging, and uncertain therapy-induced removal of cerebral amyloids in clinical trials cast doubt on this anti-Alzheimer’s antibody therapy and hence on the amyloid hypothesis, calling for a more thorough investigation of the negative impact of this type of therapy on the brain. Full article

(This article belongs to the Special Issue Breakthroughs in Diagnostic Prediction and Fundamental Therapeutics of Dementia and Movement Disorders)

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18 pages, 510 KiB

Open AccessReview

Formulating Treatment to Cure Alzheimer’s Dementia: Approach #2

by Jeffrey Fessel

Int. J. Mol. Sci. 2024, 25(6), 3524; https://doi.org/10.3390/ijms25063524 - 20 Mar 2024

Cited by 1 | Viewed by 2204

Abstract

There are two generic approaches to curing any medical condition. The first one treats every patient for all the known possible causes that contribute to pathogenesis; the second one individualizes potentially curative therapy by only identifying in each separate patient the components of pathogenesis that are actually operative and treating those. This article adopts the second approach for formulating a cure for Alzheimer’s dementia (AD). The components of AD’s pathogenesis are, in alphabetical order, as follows: circadian rhythm disturbances, depression, diabetes and insulin resistance, dyslipidemia, hypertension, inflammation, metabolic syndrome, mitochondrial dysfunction, nutritional deficiencies, TGF-β deficiency, underweight, vascular abnormalities, and Wnt/β-catenin deficiency. For each component, data are described that show the degree to which its prevalence is higher in patients with mild cognitive impairment (MCI) who did not revert to having normal cognition than in those who did because the former group is the pool of patients in which future AD may develop. Only addressing the components that are present in a particular individual potentially is a curative strategy. Published data indicate that curative therapy requires the number of such components that are addressed to be ≥3. Although structural brain changes cannot be directly addressed, the impaired neural tracts result from many of the reversible causal elements, so correcting them will benefit these tracts. Full article

(This article belongs to the Special Issue Breakthroughs in Diagnostic Prediction and Fundamental Therapeutics of Dementia and Movement Disorders)

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