Deposition Of Neurofibrillary Tangles Research Articles

Towards Early Diagnosis and Screening of Alzheimer's Disease Using Frequency Locked Whispering Gallery Mode Microtoroid Biosensors.

Alzheimer's disease (AD) is a progressive form of dementia affecting almost 55 million people worldwide. It is characterized by the abnormal deposition of amyloid plaques and neurofibrillary tangles within the brain, leading to a pathological cascade of neuron degeneration and death as well as memory loss and cognitive decline. Amyloid beta (Aβ) is an AD biomarker present in cerebrospinal fluid and blood serum and correlates with the presence of amyloid plaques and tau tangles in the brain. Measuring the levels of Aβ can help with early diagnosis of AD, which is key for studying novel AD drugs and delaying the symptoms of dementia. However, this goal is difficult to achieve due to the low levels of AD biomarkers in biofluids. Here we demonstrate for the first time the use of FLOWER (frequency locked optical whispering evanescent resonator) for quantifying the levels of post-mortem cerebrospinal fluid (CSF) Aβ42 in clinicopathologically classified control, mild cognitive impairment (MCI), and AD participants. FLOWER is capable of measuring CSF Aβ42 (area under curve, AUC = 0.92) with higher diagnostic performance than standard ELISA (AUC = 0.82) and was also able to distinguish between control and MCI samples. Our results demonstrate the capability of FLOWER for screening CSF samples for early diagnosis of Alzheimer's pathology.

P2Y1 receptor in Alzheimer's disease.

Alzheimer's disease is the most frequent form of dementia characterized by the deposition of amyloid-beta plaques and neurofibrillary tangles consisting of hyperphosphorylated tau. Targeting amyloid-beta plaques has been a primary direction for developing Alzheimer's disease treatments in the last decades. However, existing drugs targeting amyloid-beta plaques have not fully yielded the expected results in the clinic, necessitating the exploration of alternative therapeutic strategies. Increasing evidence unravels that astrocyte morphology and function alter in the brain of Alzheimer's disease patients, with dysregulated astrocytic purinergic receptors, particularly the P2Y1 receptor, all of which constitute the pathophysiology of Alzheimer's disease. These receptors are not only crucial for maintaining normal astrocyte function but are also highly implicated in neuroinflammation in Alzheimer's disease. This review delves into recent insights into the association between P2Y1 receptor and Alzheimer's disease to underscore the potential neuroprotective role of P2Y1 receptor in Alzheimer's disease by mitigating neuroinflammation, thus offering promising avenues for developing drugs for Alzheimer's disease and potentially contributing to the development of more effective treatments.

Discovery of Small Molecule Glycolytic Stimulants for Enhanced ApoE Lipidation in Alzheimer's Disease Cell Model.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by pathophysiological deposits of extracellular amyloid beta (Aβ) peptides and intracellular neurofibrillary tangles of tau. The central role of Aβ in AD pathology is well-established, with its increased deposition attributed mainly to its decreased cerebral clearance. Here, it is noteworthy that apolipoprotein E (ApoE), the most significant risk factor for AD, has been shown to play an isoform-specific role in clearing Aβ deposits (ApoE2 > ApoE3 > ApoE4), owing mainly to its lipidation status. In addition to the pathophysiological Aβ deposits, AD is also characterized by abnormal glucose metabolism, which is a distinct event preceding Aβ deposition. The present study established, for the first time, a possible link between these two major AD etiologies, with glucose metabolism directly influencing ApoE lipidation and its secretion by astrocytes expressing human ApoE4. Specifically, glucose dose-dependently activated liver X receptor (LXR), leading to elevated ABCA1 and ABCG1 protein levels and enhanced ApoE lipidation. Moreover, co-treatment with a glycolytic inhibitor significantly inhibited this LXR activation and subsequent ApoE lipidation, further supporting a central role of glucose metabolism in LXR activation leading to enhanced ApoE lipidation, which may help against AD through potential Aβ clearance. Therefore, we hypothesized that pharmacological agents that can target cellular energy metabolism, specifically aerobic glycolysis, may hold significant therapeutic potential against AD. In this context, the present study also led to the discovery of novel, small-molecule stimulants of astrocytic glucose metabolism, leading to significantly enhanced lipidation status of ApoE4 in astrocytic cells. Three such newly discovered compounds (lonidamine, phenformin, and berberine), owing to their promising cellular effect on the glycolysis-ApoE nexus, warrant further investigation in suitable in vivo models of AD.

From understanding to action: Exploring molecular connections of Down syndrome to Alzheimer's disease for targeted therapeutic approach.

Down syndrome (DS) is caused by a third copy of chromosome 21. Alzheimer's disease (AD) is a neurodegenerative condition characterized by the deposition of amyloid-beta (Aβ) plaques and neurofibrillary tangles in the brain. Both disorders have elevated Aβ, tau, dysregulated immune response, and inflammation. In people with DS, Hsa21 genes like APP and DYRK1A are overexpressed, causing an accumulation of amyloid and neurofibrillary tangles, and potentially contributing to an increased risk of AD. As a result, people with DS are a key demographic for research into AD therapeutics and prevention. The molecular links between DS and AD shed insights into the underlying causes of both diseases and highlight potential therapeutic targets. Also, using biomarkers for early diagnosis and treatment monitoring is an active area of research, and genetic screening for high-risk individuals may enable earlier intervention. Finally, the fundamental mechanistic parallels between DS and AD emphasize the necessity for continued research into effective treatments and prevention measures for DS patients at risk for AD. Genetic screening with customized therapy approaches may help the DS population in current clinical studies and future biomarkers.

Natural flavonoids as potential therapeutics in the management of Alzheimer's disease: a review.

Alzheimer's disease (AD) is an age-dependent neurodegenerative disorder which is associated with the accumulation of proteotoxic Aβ peptides, and pathologically characterized by the deposition of Aβ-enriched plaques and neurofibrillary tangles. Given the social and economic burden caused by the rising frequency of AD, there is an urgent need for the development of appropriate therapeutics. Natural compounds are gaining popularity as alternatives to synthetic drugs due to their neuroprotective properties and higher biocompatibility. While natural compound's therapeutic effects for AD have been recently investigated in numerous in vitro and in vivo studies, only few have developed to clinical trials. The present review aims to provide a brief overview of the therapeutic effects, new insights, and upcoming perspectives of the preclinical and clinical trials of flavonoids for the treatment of Alzheimer's disease.

Genetic deletion of astrocytic calcineurin B1 prevents cognitive impairment and neuropathology development in acute and chronic mouse models of Alzheimer's disease.

Alzheimer's disease (AD) represents an urgent yet unmet challenge for modern society, calling for exploration of innovative targets and therapeutic approaches. Astrocytes, main homeostatic cells in the CNS, represent promising cell-target. Our aim was to investigate if deletion of the regulatory CaNB1 subunit of calcineurin in astrocytes could mitigate AD-related memory deficits, neuropathology, and neuroinflammation. We have generated two, acute and chronic, AD mouse models with astrocytic CaNB1 ablation (ACN-KO). In the former, we evaluated the ability of β-amyloid oligomers (AβOs) to impair memory and activate glial cells once injected in the cerebral ventricle of conditional ACN-KO mice. Next, we generated a tamoxifen-inducible astrocyte-specific CaNB1 knock-out in 3xTg-AD mice (indACNKO-AD). CaNB1 was deleted, by tamoxifen injection, in 11.7-month-old 3xTg-AD mice for 4.4 months. Spatial memory was evaluated using the Barnes maze; β-amyloid plaques burden, neurofibrillary tangle deposition, reactive gliosis, and neuroinflammation were also assessed. The acute model showed that ICV injected AβOs in 2-month-old wild type mice impaired recognition memory and fostered a pro-inflammatory microglia phenotype, whereas in ACN-KO mice, AβOs were inactive. In indACNKO-AD mice, 4.4 months after CaNB1 depletion, we found preservation of spatial memory and cognitive flexibility, abolishment of amyloidosis, and reduction of neurofibrillary tangles, gliosis, and neuroinflammation. Our results suggest that ACN is crucial for the development of cognitive impairment, AD neuropathology, and neuroinflammation. Astrocyte-specific CaNB1 deletion is beneficial for both the abolishment of AβO-mediated detrimental effects and treatment of ongoing AD-related pathology, hence representing an intriguing target for AD therapy.

Novel ligand conjugated poly(propylene imine) dendrimers for brain targeted delivery of tacrine hydrochloride

Alzheimer's disease (AD) is the most common type of neurodegenerative disorder characterized by extracellular deposition of Amyloid β and intracellular deposition of neurofibrillary tangles. One of the most common etiological factors is rapid and excessive hydrolysis of acetylcholine by acetylcholinesterase (AChE) enzyme. Tacrine is one of the most potent and first USFDA approved centrally acting AChE inhibitor recommended for treatment of AD, but it is no longer in use as it causes severe peripheral side effects, mainly hepatotoxicity. In this research work, novel dendrimeric conjugates were developed with an aim of enhancing the brain targeting efficiency of tacrine and eliminating the peripheral side effects. Poly(propyleneimine) G5.0 dendrimers were conjugated with oleic acid as a brain targeting ligand, and the conjugation was confirmed by Fourier-transform infrared spectroscopy, 1H nuclear magnetic resonance spectroscopy and dynamic light scattering studies. Tacrine hydrochloride was loaded into the plain dendrimer as well as oleic acid conjugated dendrimer by physical encapsulation method. The in vitro AChE inhibitory study showed retention of the AChE inhibition ability of tacrine in dendrimeric conjugates. The safety of the drug loaded conjugates was confirmed by haemolytic, nasal ciliotoxicity and cytotoxicity studies. Further, cellular uptake studies in SH-SY5Y cells showed abundance of green cytoplasmic fluorescence, suggesting enhanced internalization of dendrimeric conjugates. The results of this research work support the further exploration of this novel dendrimers based conjugated delivery system for in vivo studies as a potential alternative to treat AD.

Imaging Neuroinflammation: Quantification of Astrocytosis in a Multitracer PET Approach.

The recent progress in the development of in vivo biomarkers is rapidly changing how neurodegenerative diseases are conceptualized and diagnosed and how clinical trials are designed today. Alzheimer's disease (AD) - the most common neurodegenerative disorder - is characterized by a complex neuropathology involving the deposition of extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) of hyperphosphorylated tau proteins, accompanied by the activation of glial cells, i.e., astrocytes and microglia, and neuroinflammatory response, leading to neurodegeneration and cognitive dysfunction. An increasing diversity of positron emission tomography (PET) imaging radiotracers is available to selectively target the different pathophysiological processes of AD. Along with the success of Aβ PET and the more recent tau PET imaging, there is a great interest to develop PET tracers to image glial reactivity and neuroinflammation. While most research to date has focused on imaging microgliosis, there is an upsurge of interest in imaging reactive astrocytes in the AD continuum. There is increasing evidence that reactive astrocytes are morphologically and functionally heterogeneous, with different subtypes that express different markers and display various homeostatic or detrimental roles across disease stages. Therefore, multiple biomarkers are desirable to unravel the complex phenomenon of reactive astrocytosis. In the field of in vivo PET imaging in AD, the research concerning reactive astrocytes has predominantly focused on targeting monoamine oxidase B (MAO-B), most often using either 11C-deuterium-L-deprenyl (11C-DED) or 18F-SMBT-1 PET tracers. Additionally, imidazoline2 binding (I2BS) sites have been imaged using 11C-BU99008 PET. Recent studies in our group using 11C-DED PET imaging suggest that astrocytosis may be present from the early stages of disease development in AD. This chapter provides a detailed description of the practical approach used for the analysis of 11C-DED PET imaging data in a multitracer PET paradigm including 11C-Pittsburgh compound B (11C-PiB) and 18F-fluorodeoxyglucose (18F-FDG). The multitracer PET approach allows investigating the comparative regional and temporal patterns of in vivo brain astrocytosis, fibrillar Aβ deposition, glucose metabolism, and brain structural changes. It may also contribute to understanding the potential role of novel plasma biomarkers of reactive astrocytes, in particular the glial fibrillary acidic protein (GFAP), at different stages of disease progression. This chapter attempts to stimulate further research in the field, including the development of novel PET tracers that may allow visualizing different aspects of the complex astrocytic and microglial response in neurodegenerative diseases. Progress in the field will contribute to the incorporation of PET imaging of glial reactivity and neuroinflammation as biomarkers with clinical application and motivate further investigation on glial cells as therapeutic targets in AD and other neurodegenerative diseases.

APOEε4 potentiates the effects of Aβ pathology on the deposition of neurofibrillary tangles via tau phosphorylation

AbstractBackgroundThe mechanisms by which the apolipoprotein E ε4 (APOEε4) allele influences Alzheimer’s disease (AD) pathophysiological progression are poorly understood. Here, we tested the association of APOEε4 carriership and amyloid‐β (Aβ) burden with longitudinal tau pathology progression.MethodWe studied 104 individuals across the aging and AD clinical spectrum from the McGill TRIAD cohort. Study participants underwent clinical assessments, APOE genotyping, magnetic resonance imaging, positron emission tomography (PET) for Aβ ([18F]AZD4694) and tau ([18F]MK6240) at baseline, as well as an additional follow‐up tau‐PET scan (mean follow‐up, 2.4 years). We further assessed longitudinal changes in tau phosphorylation (plasma phosphorylated tau at threonine 217 [p‐tau217+]), brain atrophy (gray matter density), and clinical function (clinical dementia rating scale sum of boxes).ResultWe found that APOEε4 carriership potentiates Aβ effects on longitudinal tau tangle accumulation over two years (Figure 1). Interestingly, the APOEε4‐potentiated Aβ effects on tangles were mediated by longitudinal plasma p‐tau217+ increase (Figure 2). In addition, this longitudinal tau accumulation as measured by PET was accompanied by brain atrophy and clinical decline during the follow‐up period (Figure 3).ConclusionOur results support a model in which the APOEε4 allele plays a key role in Aβ downstream effects on the aggregation of phosphorylated tau in the form of neurofibrillary tangles in the living human brain, which is a key factor in the development of dementia. These observations have important implications for the design of future trials by suggesting that the combination of therapies targeting both ApoeE4 and Aβ pathology might have the potential to synergistically halt tau progression in AD.

Microstructure of White Matter, Probed With Diffusion MRI Modeling, Reveals Distinct Correlations Between Intra‐ vs Extra‐Cellular Spaces and Tau Load

AbstractBackgroundIn Alzheimer’s disease, pathological phosphorylation of tau protein destabilizes microtubules affecting the neural cytoskeleton organization (Kolarova et al., 2012). In this study, we investigated correlates of Alzheimer’s tau pathology and white matter (WM) microstructure using diffusion MRI (dMRI) advanced models to detect tau‐related tissue changes and their trends across brain regions.MethodTen cognitively impaired subjects (age:70±7,M/F:6/4,MMSE:27.8,CI) and 11 cognitive unimpaired (age:62.4±9,M/F:1/10,CU) were recruited in the context of the COSCODE research project (Ribaldi et al., 2021). Tau standardized uptake value ratio (SUVR) was assessed from 18F‐flortaucipir PET in entorhinal, lateral‐occipital, inferior‐temporal cortex, and amygdala (reference: cerebellar crus; Mishra et al., 2017). dMRI scans were collected at 7T. WM microstructure analysis included: diffusion tensor (DTI), kurtosis tensor imaging (DKI, Jensen and Helpern, 2010), and a biophysical model of WM microstructure (WMTI‐Watson, Fig.1, Jespersen, et al., 2018). Mean values for each diffusion metric were calculated in WM ROIs of the JHU atlas (Mori et al. 2005) and correlated to tau across CI subjects (statistical significance: p<0.05).ResultCorrelation analysis showed a systematic disconnect between diffusion metrics parallel and perpendicular to the axons: RD (and MD) correlated positively with tau, while AD negatively. Similarly, RK (and MK) correlated negatively, while AK positively (Fig. 2). Higher diffusivities and lower kurtosis (perpendicular to axons) are associated with less complex tissue, while lower diffusivities and higher kurtosis (parallel to axons) are associated with a more tortuous and heterogeneous environment. The biophysical model showed that higher diffusivity in the extra‐cellular space (De,//, De, ⊥ ) was associated with higher tau, while axonal density (f) and within‐axon diffusivity (Da) correlated negatively.ConclusionThe significant correlations between tau and FA, RD, MD, RK and MK, are consistent with neurodegeneration. The positive correlation of De,//, De, ⊥ and negative correlation of f to tau confirms the axonal loss and the increase of extracellular diffusivity. Interestingly, the negative correlation of tau to water diffusivity within the axons (Da) could be explained by microtubules breakdown and intra‐axonal deposition of neurofibrillary tangles that impede water diffusion. These evidences of dMRI microstructure correlation with tau SUVR may be useful to detect the in‐vivo neurodegeneration.

APOEε4 potentiates the effects of Aβ pathology on the deposition of neurofibrillary tangles via tau phosphorylation

AbstractBackgroundThe mechanisms by which the apolipoprotein E e4 (APOEe4) allele influences Alzheimer’s disease (AD) pathophysiological progression are poorly understood. Here, we tested the association of APOEe4 carriership and amyloid‐ß (Aß) burden with longitudinal tau pathology progression.MethodWe studied 104 individuals across the aging and AD clinical spectrum from the McGill TRIAD cohort. Study participants underwent clinical assessments, APOE genotyping, magnetic resonance imaging, positron emission tomography (PET) for Aß ([18F]AZD4694) and tau ([18F]MK6240) at baseline, as well as an additional follow‐up tau‐PET scan (mean follow‐up, 2.4 years). We further assessed longitudinal changes in tau phosphorylation (plasma phosphorylated tau at threonine 217 [p‐tau217+]), brain atrophy (gray matter density), and clinical function (clinical dementia rating scale sum of boxes).ResultWe found that APOEe4 carriership potentiates Aß effects on longitudinal tau tangle accumulation over two years (Figure 1). Interestingly, the APOEe4‐potentiated Aß effects on tangles were mediated by longitudinal plasma p‐tau217+ increase (Figure 2). In addition, this longitudinal tau accumulation as measured by PET was accompanied by brain atrophy and clinical decline during the follow‐up period (Figure 3).ConclusionOur results support a model in which the APOEe4 allele plays a key role in Aß downstream effects on the aggregation of phosphorylated tau in the form of neurofibrillary tangles in the living human brain, which is a key factor in the development of dementia. These observations have important implications for the design of future trials by suggesting that the combination of therapies targeting both ApoeE4 and Aß pathology might have the potential to synergistically halt tau progression in AD.

Ameliorative effect of β‐pinene targeting mitochondrial dysfunction and oxidative stress in Alzheimer’s disease

AbstractBackgroundSporadic Alzheimer’s disease (sAD) is the most common type of dementia, characterized by the deposition of extracellular senile plaques, neurofibrillary tangles (NFTs), and neurodegeneration, leading to memory impairment and dementia. Intracerebroventricular (ICV) streptozotocin (STZ) mimics sporadic Alzheimer’s disease (sAD) characterized by neurodegeneration arising from oxidative stress, and mitochondrial dysfunction. β‐pinene is a monoterpene having antioxidant properties interlinked with mitochondrial functioning. To study the neuroprotective and cognitive enhancement properties of β‐pinene on mitochondrial dysfunction, oxidative stress, and histological changes in an animal model of Alzheimer’s disease induced by ICV‐STZ.MethodTo establish the sAD model, intracerebroventricular (ICV) streptozotocin (STZ) at a dose of 3 mg/kg was administered bilaterally in rats on a stereotaxic apparatus. Behavioral tests such as Morris water maze (MWM), novel object recognition (NOR) and Actophotometer were performed to evaluate spatial & recognition memory and locomotor functions. Three treatment doses (50mg/kg, 100 mg/kg and 200mg/kg) of Beta pinene (β‐pinene) and Galantamine (2 mg/kg) as a reference drug were given orally to ICV‐STZ induced rats for 21 days. Cortical and hippocampal tissues were dissected. Estimation of oxidative stress, mitochondrial dysfunction as complex I, II, III, IV activity and acetylcholinesterase activity were performed for cholinergic function. Moreover, histopathology was evaluated by hematoxylin and eosin (H&E) staining.Resultβ‐pinene treatment attenuated ICV‐STZ‐induced cognitive impairment in MWM and NOR. There is no significant effect revealed on locomotor activities. Moreover, in the cortex and hippocampal area of the brain, Mitochondrial enzyme complex I, II, III, and IV, and acetylcholinesterase (AchE) activities were normalized. Furthermore, reduced glutathione (GSH), catalase, superoxide dismutase (SOD), and (Lipid peroxidation) LPO were also reversed. β‐pinene prevents neurodegeneration as examined in histopathology.ConclusionIn the ICV‐STZ rat model, β‐pinene was found to be neuroprotective by reducing oxidative stress and mitochondrial dysfunction, consequently enhancing cognitive functions indicated in the behavioral outcomes.

Nicotinic acid modulates microglial TREM-2 gene in Phytohaemagglutinin-Induced in vitro model of Alzheimer’s disease like pathology

Alzheimer’s disease (AD) is a multifactorial,neurodegenerative disorder linked withextracellular amyloid beta (Aβ) plaques deposition and formation of intracellular neurofibrillary tangles (NFTs). Currently, no effective therapies are available to cure AD. Neuroinflammation isa well-known hallmark in the onset and advancement of AD and triggering receptor expressed on myeloid cells-2 (TREM-2), a microglial gene, is responsible for regulating inflammatory responses and clearance of cellular debris. Loss of TREM-2functionincreases neuroinflammation associated expression of pro-inflammatory markersthus resultingin reduced clearance of Aβ that further aid in disease progression.Therefore, targeting neuroinflammation is a good therapeutic approach for AD. This study aimed to determine the neuroprotective effect of nicotinic acid (NA) in vitro model of AD-like pathology induced in F-98 cell line using Phytohemagglutinin (PHA). MTT assay was employed for checking the cell viability as well as the proliferation of the cells following treatment with NA. PHA at the concentration of 10 μg/mL produces maximum plaques. The neuroprotective effect of NA was next evaluated against PHA-induced plaques and it was observed that NA reverses the damages induced by PHA i.e., by inhibiting the clustering of the cells and replacing the damaged cells with the new ones. Further, NA also increased the expression of TREM-2/DAP-12 with parallel decreased in the expression of IL-1β, TNF-α and iNOS. It also successfully altered disease associated ADAM-10 and BACE-1 compared to PHA control. These findings suggest that NA might be considered as a good therapeutic candidate for the treatment of neurodegenerative disorders like AD.

Terahertz Irradiation Improves Cognitive Impairments and Attenuates Alzheimer’s Neuropathology in the APPSWE/PS1DE9 Mouse: A Novel Therapeutic Intervention for Alzheimer’s Disease

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the deposition of amyloid-β (Aβ), neurofibrillary tangles, neuroinflammation, and neurodegeneration in the brain. In recent years, considering the unsatisfied benefits of pharmacological therapies, non-pharmacological therapy has become a research hotspot for AD intervention. Terahertz (THz) waves with a range between microwave and infrared regions in the electromagnetic spectrum and high permeability to a wide range of materials have great potential in the bioengineering field. However, its biological impacts on the central nervous system, under either physiological or pathological conditions, are poorly investigated. In this study, we first measured the 0.14 THz waves penetration across the skull of a C57BL/6 mouse and found the percentage of THz penetration to be ~70%, guaranteeing that THz waves can reach the relevant brain regions. We then exposed the APPSWE/PS1DE9 mouse model of AD to repeated low-frequency THz waves on the head. We demonstrated that THz waves treatment significantly improved the cognitive impairment and alleviated AD neuropathology including Aβ deposition and tau hyperphosphorylation in the AD mice. Moreover, THz waves treatment effectively attenuated mitochondrial impairment, neuroinflammation, and neuronal loss in the AD mouse brain. Our findings reveal previously unappreciated beneficial effects of THz waves treatment in AD and suggest that THz waves may have the potential to be used as a novel therapeutic intervention for this devastating disease.

Targeting dopamine transporter to ameliorate cognitive deficits in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by the pathologic deposition of amyloid and neurofibrillary tangles in the brain, leading to neuronal damage and defective synapses. These changes manifest as abnormalities in cognition and behavior. The functional deficits are also attributed to abnormalities in multiple neurotransmitter systems contributing to neuronal dysfunction. One such important system is the dopaminergic system. It plays a crucial role in modulating movement, cognition, and behavior while connecting various brain areas and influencing other neurotransmitter systems, making it relevant in neurodegenerative disorders like AD and Parkinson's disease (PD). Considering its significance, the dopaminergic system has emerged as a promising target for alleviating movement and cognitive deficits in PD and AD, respectively. Extensive research has been conducted on dopaminergic neurons, receptors, and dopamine levels as critical factors in cognition and memory in AD. However, the exact nature of movement abnormalities and other features of extrapyramidal symptoms are not fully understood yet in AD. Recently, a previously overlooked element of the dopaminergic system, the dopamine transporter, has shown significant promise as a more effective target for enhancing cognition while addressing dopaminergic system dysfunction in AD.

Fractal Dimension Analyses to Detect Alzheimer’s and Parkinson’s Diseases Using Their Thin Brain Tissue Samples via Transmission Optical Microscopy

Biological tissues in nature are fractal due to their self-similarity and porosity properties. These properties change with the progress of some diseases, including brain tissue in leading neurological disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Thus, there is an unmet clinical need to develop a tool for accurate and early diagnosis of AD and PD conditions. Although the whole brain tissues in AD and PD have been extensively studied, their local structural alterations at the nano-to-submicron levels have not been explored. In this paper, we measure the local structural alterations in different brain regions of AD and PD patients by measuring their change in fractal dimensions via optical microscopy. Our results show an increase in the fractal dimension value of ~5–10% in the affected regions of the brain tissues relative to their respective controls. For AD cases, the structural alteration is attributed to the aberrant deposition of amyloid beta protein and neurofibrillary tangles in the brain, and for PD, the gradual loss of dopaminergic neurons and abnormal accumulation of α-synuclein in the brain. The work will enhance the further understanding of alterations in the brain structures in AD and PD and its detection.

Biomarkers and Risk Assessment of Alzheimer's Disease in Low- and Middle-Income Countries.

Dementia is a chronic syndrome which is common among the elderly and is associated with significant morbidity and mortality for patients and their caregivers. Alzheimer's disease (AD), the most common form of clinical dementia, is biologically characterized by the deposition of amyloid-β plaques and neurofibrillary tangles in the brain. The onset of AD begins decades before manifestation of symptoms and clinical diagnosis, underlining the need to shift from clinical diagnosis of AD to a more objective diagnosis using biomarkers. Having performed a literature search of original articles and reviews on PubMed and Google Scholar, we present this review detailing the existing biomarkers and risk assessment tools for AD. The prevalence of dementia in low- and middle-income countries (LMICs) is predicted to increase over the next couple of years. Thus, we aimed to identify potential biomarkers that may be appropriate for use in LMICs, considering the following factors: sensitivity, specificity, invasiveness, and affordability of the biomarkers. We also explored risk assessment tools and the potential use of artificial intelligence/machine learning solutions for diagnosing, assessing risks, and monitoring the progression of AD in low-resource settings. Routine use of AD biomarkers has yet to gain sufficient ground in clinical settings. Therefore, clinical diagnosis of AD will remain the mainstay in LMICs for the foreseeable future. Efforts should be made towards the development of low-cost, easily administered risk assessment tools to identify individuals who are at risk of AD in the population. We recommend that stakeholders invest in education, research and development targeted towards effective risk assessment and management.

PET image denoising based on denoising diffusion probabilistic model.

Due to various physical degradation factors and limited counts received, PET image quality needs further improvements. The denoising diffusion probabilistic model (DDPM) was a distribution learning-based model, which tried to transform a normal distribution into a specific data distribution based on iterative refinements. In this work, we proposed and evaluated different DDPM-based methods for PET image denoising. Under the DDPM framework, one way to perform PET image denoising was to provide the PET image and/or the prior image as the input. Another way was to supply the prior image as the network input with the PET image included in the refinement steps, which could fit for scenarios of different noise levels. 150 brain [[Formula: see text]F]FDG datasets and 140 brain [[Formula: see text]F]MK-6240 (imaging neurofibrillary tangles deposition) datasets were utilized to evaluate the proposed DDPM-based methods. Quantification showed that the DDPM-based frameworks with PET information included generated better results than the nonlocal mean, Unet and generative adversarial network (GAN)-based denoising methods. Adding additional MR prior in the model helped achieved better performance and further reduced the uncertainty during image denoising. Solely relying on MR prior while ignoring the PET information resulted in large bias. Regional and surface quantification showed that employing MR prior as the network input while embedding PET image as a data-consistency constraint during inference achieved the best performance. DDPM-based PET image denoising is a flexible framework, which can efficiently utilize prior information and achieve better performance than the nonlocal mean, Unet and GAN-based denoising methods.

Modulating the RAGE-Induced Inflammatory Response: Peptoids as RAGE Antagonists.

While the primary pathology of Alzheimer's disease (AD) is defined by brain deposition of amyloid-β (Aβ) plaques and tau neurofibrillary tangles, chronic inflammation has emerged as an important factor in AD etiology. Upregulated cell surface expression of the receptor for advanced glycation end-products (RAGE), a key receptor of innate immune response, is reported in AD. In parallel, RAGE ligands, including Aβ aggregates, HMGB1, and S100B, are elevated in AD brain. Activation of RAGE by these ligands triggers release of inflammatory cytokines and upregulates cell surface RAGE. Despite such observation, there are currently no therapeutics that target RAGE for treatment of AD-associated neuroinflammation. Peptoids, a novel class of potential AD therapeutics, display low toxicity, facile blood-brain barrier permeability, and resistance to proteolytic degradation. In the current study, peptoids were designed to mimic Aβ, a ligand that binds the V-domain of RAGE, and curtail RAGE inflammatory activation. We reveal the nanomolar binding capability of peptoids JPT1 and JPT1a to RAGE and demonstrate their ability to attenuate lipopolysaccharide-induced pro-inflammatory cytokine production as well as upregulation of RAGE cell surface expression. These results support RAGE antagonist peptoid-based mimics as a prospective therapeutic strategy to counter neuroinflammation in AD and other neurodegenerative diseases.

Chemical Underpinnings of Alzheimer’s Disease Symptoms and Causative Factors: A Systematic Review

The brain depends on a complex network of chemical interactions to maintain its homeostasis and functionality. Accordingly, the pathology of neurodegenerative diseases, such as Alzheimer’s disease (AD), has been shown to disrupt the chemical mechanisms that support the brain to carry out its degenerative effect. However, the nature of these disruptions remain elusive. AD is biologically defined by the deposition of Amyloid-Beta (Aβ) plaques and tau neurofibrillary tangles, and has been shown to be strongly correlated with the expression of the Apolipoprotein E4 (ApoE4) allele. Recent findings in the field of neurochemistry indicate the chemical underpinnings of hallmark signs of AD. This review will discuss the process of pathogenesis of AD, from the formation to the causal effects of AD markers, through a chemical lens. The fibrillization of Aβ isoforms as well as the fluent molecular mixing of tau isoforms and hyperphosphorylation of tau observed in mouse lines are discussed as precursor processes to Aβ plaques and tau neurofibrillary tangles. Furthermore, the pathology of Aβ plaques through redox chemistry in the brain, tau neurofibrillary tangles through microtubule disassembly, and ApoE4 through reactive oxygen species (ROS) formation are also presented. Current therapeutic approaches targeted towards specific facets of AD, such as Aducanumab, have found moderate success in treatment, and this progress indicates neurochemical pathways as a potential target for future therapeutic procedures to counteract the degenerative effects of AD.