Clinical Symptoms Of Alzheimer's Disease Research Articles

Crystal Violet Selectively Detects Aβ Oligomers but Not Fibrils In Vitro and in Alzheimer's Disease Brain Tissue.

Deposition of extracellular Amyloid Beta (Aβ) and intracellular tau fibrils in post-mortem brains remains the only way to conclusively confirm cases of Alzheimer's Disease (AD). Substantial evidence, though, implicates small globular oligomers instead of fibrils as relevant biomarkers of, and critical contributors to, the clinical symptoms of AD. Efforts to verify and utilize amyloid oligomers as AD biomarkers in vivo have been limited by the near-exclusive dependence on conformation-selective antibodies for oligomer detection. While antibodies have yielded critical evidence for the role of both Aβ and tau oligomers in AD, they are not suitable for imaging amyloid oligomers in vivo. Therefore, it would be desirable to identify a set of oligomer-selective small molecules for subsequent development into Positron Emission Tomography (PET) probes. Using a kinetics-based screening assay, we confirm that the triarylmethane dye Crystal Violet (CV) is oligomer-selective for Aβ42 oligomers (AβOs) grown under near-physiological solution conditions in vitro. In postmortem brains of an AD mouse model and human AD patients, we demonstrate that A11 antibody-positive oligomers but not Thioflavin S (ThioS)-positive fibrils colocalize with CV staining, confirming in vitro results. Therefore, our kinetic screen represents a robust approach for identifying new classes of small molecules as candidates for oligomer-selective dyes (OSDs). Such OSDs, in turn, provide promising starting points for the development of PET probes for pre-mortem imaging of oligomer deposits in humans.

Monitoring synaptic pathology in Alzheimer's disease through fluid and PET imaging biomarkers: a comprehensive review and future perspectives.

Alzheimer's disease (AD) is currently constrained by limited clinical treatment options. The initial pathophysiological event, which can be traced back to decades before the clinical symptoms become apparent, involves the excessive accumulation of amyloid-beta (Aβ), a peptide comprised of 40-42 amino acids, in extraneuronal plaques within the brain. Biochemical and histological studies have shown that overaccumulation of Aβ instigates an aberrant escalation in the phosphorylation and secretion of tau, a microtubule-binding axonal protein. The accumulation of hyperphosphorylated tau into intraneuronal neurofibrillary tangles is in turn correlated with microglial dysfunction and reactive astrocytosis, culminating in synaptic dysfunction and neurodegeneration. As neurodegeneration progresses, it gives rise to mild clinical symptoms of AD, which may eventually evolve into overt dementia. Synaptic loss in AD may develop even before tau alteration and in response to possible elevations in soluble oligomeric forms of Aβ associated with early AD. These findings largely rely on post-mortem autopsy examinations, which typically involve a limited number of patients. Over the past decade, a range of fluid biomarkers such as neurogranin, α-synuclein, visinin-like protein 1 (VILIP-1), neuronal pentraxin 2, and β-synuclein, along with positron emission tomography (PET) markers like synaptic vesicle glycoprotein 2A, have been developed. These advancements have facilitated the exploration of how synaptic markers in AD patients correlate with cognitive impairment. However, fluid biomarkers indicating synaptic loss have only been validated in cerebrospinal fluid (CSF), not in plasma, with the exception of VILIP-1. The most promising PET radiotracer, [11C]UCB-J, currently faces significant challenges hindering its widespread clinical use, primarily due to the necessity of a cyclotron. As such, additional research geared toward the exploration of synaptic pathology biomarkers is crucial. This will not only enable their extensive clinical application, but also refine the optimization process of AD pharmacological trials.

Plasma tau phosphorylation at T217 predicts amyloid deposition in dominantly inherited and late onset Alzheimer disease participants without clinical symptoms

AbstractBackgroundProgressive amyloid plaque accumulation in the brain precedes the emergence of clinical symptoms in Alzheimer disease (AD). This asymptomatic phase, referred to as preclinical AD, induces significant modification of tau phosphorylation in the cerebrospinal fluid (CSF). CSF tau phosphorylation occupancy at Threonine 217 (T217) becomes abnormal more than 20 years before cognitive decline in dominantly inherited AD (DIAD). CSF hyperphosphorylation at T217 also associates with amyloid pathology in late‐onset AD (LOAD) individuals with preclinical AD. In this study, we examined the performance of plasma T217 phosphorylation to detect amyloid plaques deposition measured by amyloid‐PET in asymptomatic participants with DIAD or late‐onset AD (LOAD).MethodWe measured plasma T217 phosphorylation using tau immunoprecipitation and high‐resolution mass spectrometry. Phosphorylation abundance at T217 was expressed as p‐tau217 ratio defined using the level of T217 phosphorylated tau peptide normalized to total tau level. The DIAD cohort included 355 samples from 176 CDR0 and 51 CDR>0 participants in the DIAN Observational study with 62% mutation carriers, all collected in relation to the estimated years to symptom onset (EYO). The LOAD cohort included 321 cross‐sectional samples from BioFINDER‐2 study. Amyloid positivity was determined using cross sectional amyloid‐PET scan available for each participant.ResultWe observed abnormal plasma p‐tau217 ratio in DIAD mutation carriers more than 15 years before EYO (Figure 1). Plasma p‐tau217 ratio accurately predicted amyloid PET positivity for individuals across multiple preclinical stages (Table 1, AUC respectively 0.89 and 0.98 for EYO brackets ‐20 to ‐10 and ‐10 to 0). The plasma test had similar performance in distinguishing amyloid status in the DIAD and the LOAD cohorts (AUC respectively 0.96 and 0.97, Table 1). In LOAD, plasma p‐tau217 ratio identified amyloid positivity independently of the cognitive status (AUC respectively 0.96 and 0.97 for asymptomatic and symptomatic).ConclusionOur results support the use of plasma p‐tau217 ratio to screen cognitively normal populations at risk of developing AD dementia. This blood‐based biomarker can support the recruitment of asymptomatic participants for prevention trials and help identifying patients who might benefit from early care using future AD drugs more than a decade before the detection of cognitive symptoms.

Ketone bodies mediate alterations in brain energy metabolism and biomarkers of Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia. AD is a progressive neurodegenerative disorder characterized by cognitive dysfunction, including learning and memory deficits, and behavioral changes. Neuropathology hallmarks of AD such as amyloid beta (Aβ) plaques and neurofibrillary tangles containing the neuron-specific protein tau is associated with changes in fluid biomarkers including Aβ, phosphorylated tau (p-tau)-181, p-tau 231, p-tau 217, glial fibrillary acidic protein (GFAP), and neurofilament light (NFL). Another pathological feature of AD is neural damage and hyperactivation of astrocytes, that can cause increased pro-inflammatory mediators and oxidative stress. In addition, reduced brain glucose metabolism and mitochondrial dysfunction appears up to 15 years before the onset of clinical AD symptoms. As glucose utilization is compromised in the brain of patients with AD, ketone bodies (KBs) may serve as an alternative source of energy. KBs are generated from the β-oxidation of fatty acids, which are enhanced following consumption of ketogenic diets with high fat, moderate protein, and low carbohydrate. KBs have been shown to cross the blood brain barrier to improve brain energy metabolism. This review comprehensively summarizes the current literature on how increasing KBs support brain energy metabolism. In addition, for the first time, this review discusses the effects of ketogenic diet on the putative AD biomarkers such as Aβ, tau (mainly p-tau 181), GFAP, and NFL, and discusses the role of KBs on neuroinflammation, oxidative stress, and mitochondrial metabolism.

Identification of Cholinesterase Inhibitors and Antioxidant Molecules from Leaf of Clerodendrum splendens G. Don (Verbenaceae) Using GC-MS

More than half of people with dementia globally have Alzheimer's disease (AD). Memory and cognitive impairment is one of the clinical symptoms of AD. Currently there is no cure for AD; hence the need arises to search for new neurotherapeutic agent. The rationale of this research is to identify molecules with cholinesterase inhibition and antioxidant potential from Clerodendrum splendens using GC-MS. The powdered leaves of Clerodendrum splendens G.Don (Verbenaceae) was extracted by successive method. Cholinesterase inhibitory activities were measured according to Ellman's method. Antioxidant capacity was assessed using standard in vitro chemical analysis and bioactive compounds were identified using GC-MS analysis. The ethyl acetate fraction showed the highest acetylcholinesterase inhibitory activity at 1 mg/mL with IC50 of 0.42±0.01 mg/mL (81.11±1.7%) in comparism with eserine (IC50 of 0.050±0.01 mg/mL). The ethyl acetate fraction at 1 mg/mL also showed good metal chelating activity (IC50 of 0.287±0.02 mg/mL) in comparism with EDTA (IC50 = 0.086±0.00 mg/mL). The ethyl acetate fraction showed highest nitric oxide scavenging activity (IC50 of 0.564±0.1 mg/mL) when compared to ascorbic acid (IC50 of 0.064±0.06 mg/mL). The total anthocyanin was higher in ethyl acetate fraction (52.184±2.0 mg cyanidin 3-glucoside/100g of sample). The GC-MS analysis of the ethyl acetate fraction revealed fifty-eight (58) compounds which include 9,12- Octadecadienoic acid (Z,Z)- (RT-15.974, 13.56%), n-Hexadecanoic acid (RT-14.802, 8.88%). Molecules identified by GC-MS from the ethyl acetate fraction could be possible drug lead for the treatment of AD.

Oxidative Stress and Aging as Risk Factors for Alzheimer's Disease and Parkinson's Disease: The Role of the Antioxidant Melatonin.

Aging and neurodegenerative diseases share common hallmarks, including mitochondrial dysfunction and protein aggregation. Moreover, one of the major issues of the demographic crisis today is related to the progressive rise in costs for care and maintenance of the standard living condition of aged patients with neurodegenerative diseases. There is a divergence in the etiology of neurodegenerative diseases. Still, a disturbed endogenous pro-oxidants/antioxidants balance is considered the crucial detrimental factor that makes the brain vulnerable to aging and progressive neurodegeneration. The present review focuses on the complex relationships between oxidative stress, autophagy, and the two of the most frequent neurodegenerative diseases associated with aging, Alzheimer's disease (AD) and Parkinson's disease (PD). Most of the available data support the hypothesis that a disturbed antioxidant defense system is a prerequisite for developing pathogenesis and clinical symptoms of ADs and PD. Furthermore, the release of the endogenous hormone melatonin from the pineal gland progressively diminishes with aging, and people's susceptibility to these diseases increases with age. Elucidation of the underlying mechanisms involved in deleterious conditions predisposing to neurodegeneration in aging, including the diminished role of melatonin, is important for elaborating precise treatment strategies for the pathogenesis of AD and PD.

Current emerging novel therapies for Alzheimer's disease and the future prospects of magneto-mechanical force therapy.

Alzheimer's disease (AD) is the most common neurodegenerative disease among the elderly, and the morbidity increases with the aging population aggravation. The clinical symptoms of AD mainly include cognitive impairment and memory loss, which undoubtedly bring a huge burden to families and society. Currently, the drugs in clinical use only improve the symptoms of AD but do not cure or prevent the progression of the disease. Therefore, it is urgent for us to develop novel therapeutic strategies for effective AD treatment. To provide a better theoretical basis for exploring novel therapeutic strategies in future AD treatment, this review introduces the recent AD treatment technologies from three aspects, including nanoparticle (NP) based drug therapy, biological therapy and physical therapy. The nanoparticle-mediated therapeutic approaches at the nanomaterial-neural interface and biological system are described in detail, and in particular the magneto-regulated strategies by magnetic field actuating magnetic nanoparticles are highlighted. Promising application of magneto-mechanical force regulated strategy in future AD treatment is also addressed, which offer possibilities for the remote manipulation in a precise manner. In the future, it may be possible for physicians to realize a remote, precise and effective therapy for AD using magneto-mechanical force regulated technology based on the combination of magnetic nanoparticles and an external magnetic field.

Serum Beta-Synuclein Is Higher in Down Syndrome and Precedes Rise of pTau181.

This exploratory case-control study investigates the synaptic marker beta-synuclein in serum and plasma pTau181 in adults with Down syndrome (DS) with (sDS, n= 14) and without (aDS, n= 47) clinical symptoms of Alzheimer disease (AD) as well as euploid controls (n= 23). Beta-synuclein was higher in aDS and more pronounced in sDS (p< 0.0001), whereas pTau181 was only higher in sDS (p< 0.0001). Both markers showed good discriminatory power (area under the curve > 0.90) to distinguish symptomatic from asymptomatic AD. The data indicate that synaptic alterations belong to the earliest AD-associated events in DS and highlight the value of serum beta-synuclein as a potential early marker of AD. ANN NEUROL 2022;92:6-10.

Altered Biological Rhythm and Alzheimer's Disease: A Bidirectional Relationship.

Biological rhythms have become the research focus in recent years. Biological rhythm disruption is a common symptom of Alzheimer's disease (AD) patients, which is usually considered as the late consequence of AD. Recent studies have shown that biological rhythm disruption even occurs before the onset of clinical symptoms of AD. The causal relationship between AD and biological rhythm disruption is not clear. Delineating their relationship can help understand the disease mechanisms and make the early diagnosis of AD possible. This review integrates the research on the abnormal changes of the biological rhythm-related parameters in the clinical manifestations of AD patients and the roles of the biological rhythm disorders in AD. We will discuss the links between biological rhythms and AD, with the focus on the bidirectionality between biological rhythms and AD processes. Collectively, these updated research findings may provide the basis for further exploring the significance of rhythm in the diagnosis and treatment of AD.

Subtle genomic DNA damage induces intraneuronal production of amyloid-β (1-42) by increasing β-secretase activity.

Aberrant accumulation of amyloid-β (Aβ) in brain is the major trigger for pathogenesis in Alzheimer's disease (AD). It is imperative to understand how Aβ attains such toxic levels in the brain parenchyma. We detected that a subtle and tolerable amount of DNA damage, related to aging, increased intraneuronal Aβ1-42 production both in cultured neuron and in cortex of rodent brain. Strikingly, we also observed elevated levels of mitochondrial fusion and of its major driver protein, MFN2. Hyperfusion of mitochondria may be seen as an adaptive stress response resulting from the induction of ER stress since we detected the activation of both PERK and IRE1α arms of unfolded protein response of ER stress. We found increased phosphorylation of PERK substrate eukaryotic initiation factor 2 α (eIF2α), and upregulation of the downstream effector proteins, ATF4 and CHOP. Concomitantly, increased XBP1 level, the direct effecter protein of IRE-1α, was observed. Reports suggest that eIF2α phosphorylation can increase BACE1 activity, the rate limiting enzyme in Aβ production. Here, we show that inhibiting PERK, decreased Aβ1-42 level while direct BACE1 inhibition, reduced the mitochondrial fusion. We found increased MFN2 expression in young 5xFAD mice when Aβ plaques and neurodegeneration were absent. Thus, our study indicates that mild DNA damage leads to increased Aβ1-42 production almost as a consequence of an initial ER stress-directed protective mitochondrial fusion in brain. We propose that an age-related subtle genomic DNA damage may trigger enhanced intraneuronal Aβ1-42 production in an apparently healthy neuron way before the appearance of clinical symptoms in AD.

Clinical features and brain structural changes in magnetic resonance imaging in Alzheimer's disease patients with apathy.

Background: Apathy is common in Alzheimer’s disease (AD) patients. However, its relation with other clinical symptoms in AD and brain structural changes in magnetic resonance imaging is unclear.Results: Compared with AD with no apathy group, cognitive function and activities of daily living were significantly impaired and neuropsychiatric symptoms were obviously presented in AD with apathy group (P<0.05). The frequency of Apolipoprotein E genotypes was not significantly different (P>0.05). Correlation analyses and multiple linear analyses revealed that thickness of left temporal pole and volume of posterior corpus callosum were significantly and negatively correlated with Modified Apathy Estimation Scale score in AD patients (P<0.05).Conclusions: Apathy with AD is positively correlated with cognitive impairment, neuropsychiatric symptoms and poor activities of daily living. Atrophy of left temporal pole and posterior corpus callosum presented by MRI is positively related with apathy of AD.Methods: In this study, 137 AD patients were recruited and divided into AD with apathy group and AD with no apathy group according to Modified Apathy Estimation Scale score. We evaluated patients’ cognitive function, neuropsychiatric symptoms and activities of daily living, detected the frequency of Apolipoprotein E genotypes and measured cortical thickness and volume by magnetic resonance imaging (MRI).

Connecting Mind-Body Therapy-Mediated Effects to Pathological Features of Alzheimer's Disease.

Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder that represents a major and increasing global health challenge. In most cases, the first clinical symptoms of AD are preceded by neuropathological changes in the brain that develop years to decades before their onset. Therefore, research in the last years has focused on this preclinical stage of AD trying to discover intervention strategies that might, if implemented effectively, delay or prevent disease progression. Among those strategies, mind-body therapies such as yoga and meditation have gained increasing interest as complementary alternative interventions. Several studies have reported a positive impact of yoga and meditation on brain health in both healthy older adults and dementia patients. However, the underlying neurobiological mechanisms contributing to these effects are currently not known in detail. More specifically, it is not known whether yogic interventions, directly or indirectly, can modulate risk factors or pathological mechanisms involved in the development of dementia. In this article, we first review the literature on the effects of yogic practices on outcomes such as cognitive functioning and neuropsychiatric symptoms in patients with mild cognitive impairment and dementia. Then, we analyze how yogic interventions affect different risk factors as well as aspects of AD pathophysiology based on observations of studies in healthy individuals or subjects with other conditions than dementia. Finally, we integrate this evidence and propose possible mechanisms that might explain the positive effects of yogic interventions in cognitively impaired individuals.

Prediction of Alzheimer's Disease Progression with Multi-Information Generative Adversarial Network.

Alzheimer's disease (AD) is a chronic neurodegenerative disease, and its long-term progression prediction is definitely important. The structural Magnetic Resonance Imaging (sMRI) can be used to characterize the cortical atrophy that is closely coupled with clinical symptoms in AD and its prodromal stages. Many existing methods have focused on predicting the cognitive scores at future time-points using a set of morphological features derived from sMRI. The 3D sMRI can provide more massive information than the cognitive scores. However, very few works consider to predict an individual brain MRI image at future time-points. In this article, we propose a disease progression prediction framework that comprises a 3D multi-information generative adversarial network (mi-GAN) to predict what one's whole brain will look like with an interval, and a 3D DenseNet based multi-class classification network optimized with a focal loss to determine the clinical stage of the estimated brain. The mi-GAN can generate high-quality individual 3D brain MRI image conditioning on the individual 3D brain sMRI and multi-information at the baseline time-point. Experiments are implemented on the Alzheimer's Disease Neuroimaging Initiative (ADNI). Our mi-GAN shows the state-of-the-art performance with the structural similarity index (SSIM) of 0.943 between the real MRI images at the fourth year and the generated ones. With mi-GAN and focal loss, the pMCI vs. sMCI accuracy achieves 6.04% improvement in comparison with conditional GAN and cross entropy loss.

Asymmetric Differences in the Gray Matter Volume and Functional Connections of the Amygdala Are Associated With Clinical Manifestations of Alzheimer's Disease.

ObjectiveAsymmetry is a subtle but pervasive aspect of the human brain, which may be altered in several neuropsychiatric conditions. Magnetic resonance imaging (MRI) studies have reported that cerebral structural asymmetries are altered in Alzheimer’s disease (AD), but most of these studies were conducted at the region-of-interest level. At the functional level, there are few reports of resting-state functional asymmetries based on functional MRI. In this study, we investigated lateral differences in structural volumes and strengths of functional connectivity between individuals with AD and healthy controls (HCs) at the voxel level.MethodsForty-eight patients with AD and 32 matched HCs were assessed. An analysis of voxel-based morphometry (VBM) of gray matter volume was performed at the whole-brain level to explore anatomical cerebral asymmetries in AD. We then performed a seed-to-whole-brain functional connectivity (FC) analysis to reveal FC asymmetries in AD. An asymmetry index (AI) was used to measure these changes, and the relationship between the structural and functional AIs and the clinical symptoms of AD was explored.ResultsA VBM analysis revealed a rightward and a leftward lateralization in the amygdala and the thalamus, respectively, in patients with AD. FC between the amygdala and the precuneus showed a rightward lateralization in AD, which was the opposite of the lateralization in the HCs. The asymmetric changes in structure and function were associated with disease severity and functional impairment in AD.ConclusionOur study highlights the value of considering asymmetries in the amygdala and the thalamus in clinical evaluations and their relevance to clinical measures.

Development of a PET radioligand selective for cerebral amyloid angiopathy

IntroductionPositron emission tomography (PET) using radiolabeled amyloid-binding compounds has advanced the field of Alzheimer's disease (AD) by enabling detection and longitudinal tracking of fibrillar amyloid-β (Aβ) deposits in living people. However, this technique cannot distinguish between Aβ deposits in brain parenchyma (amyloid plaques) from those in blood vessels (cerebral amyloid angiopathy, CAA). Development of a PET radioligand capable of selectively detecting CAA would help clarify its contribution to global brain amyloidosis and clinical symptoms in AD and would help to characterize side-effects of anti-Aβ immunotherapies in AD patients, such as CAA. MethodsA candidate CAA-selective compound (1) from a panel of analogues of the amyloid-binding dye Congo red was synthesized. The binding affinity to Aβ fibrils and lipophilicity of compound 1 were determined and selectivity for CAA versus parenchymal plaque deposits was assessed ex-vivo and in-vivo in transgenic APP/PS1 mice and in postmortem human brain affected with AD pathology. ResultsCompound 1 displays characteristics of Aβ binding dyes, such as thioflavin-S, in that it labels both parenchymal Aβ plaques and CAA when applied to histological sections from both a transgenic APP/PS1 mouse model of Aβ amyloidosis and AD brain. Thus, compound 1 lacks molecular selectivity to distinguish Aβ deposits in CAA from those in plaques. However, when administered to living APP/PS1 mice intravenously, compound 1 preferentially labels CAA when assessed using in-vivo two-photon microscopy and ex-vivo histology and autoradiography. ConclusionWe hypothesize that selectivity of compound 1 for CAA is attributable to its limited penetration of the blood-brain barrier due to the highly polar nature of the carboxylate moiety, thereby limiting access to parenchymal plaques and promoting selective in-vivo labeling of Aβ deposits in the vascular wall (i.e., “delivery selectivity”).

Deficits in Spontaneous Cognition as an Early Marker of Alzheimer's Disease.

In the absence of a pharmacological cure, finding the most sensitive early cognitive markers of Alzheimer's disease (AD) is becoming increasingly important. In this article we review evidence showing that brain mechanisms of spontaneous, but stimulus-dependent, cognition overlap with key hubs of the default mode network (DMN) that become compromised by amyloid pathology years before the clinical symptoms of AD. This leads to the formulation of a novel hypothesis which predicts that spontaneous, but stimulus-dependent, conscious retrieval processes, that are generally intact in healthy aging, will be particularly compromised in people at the earliest stages of AD. Initial evidence for this hypothesis is presented across diverse experimental paradigms (e.g., prospective memory, mind-wandering), and new avenues for research in this area are outlined.

Aging and Alzheimer's disease pathology.

The number of people with dementia worldwide is predicted to increase to 131.5 million by 2050. When studying dementia, understanding the basis of the neuropathological background is very important. Taking Alzheimer's disease (AD) neuropathology as an example, we know that the accumulation of abnormal structures such as senile plaques and neurofibrillary tangles is a hallmark. Macroscopic atrophy affects the entorhinal area and hippocampus, amygdala, and associative regions of the neocortex. Braak advocates the spread of tau deposits from the entorhinal to associative regions of the neocortex as the disease progresses. If the AD has only tau pathology, the degree and distribution of tau deposition may be associated with clinical symptoms. However, AD is also accompanied by amyloid-β deposition and even atrophy. Although it is possible to make a neuropathological diagnosis of AD from the spread of amyloid and tau depositions, neuropathological abnormal protein accumulation cannot explain all clinical symptoms of AD. There is an ambiguity between clinical symptoms and neuropathological findings. It is important to understand neuropathological findings while understanding that this ambiguity exists. So, for the reader's help, first we briefly explain the changes in the brain with age, and then describe AD as a typical disease of dementia; finally we will describe the diseases that mimic AD for neurologists who are not experts in neuropathology.

A Comparative Analysis of the Treatment of Decision-Making by or for Patients with Neurodegenerative Diseases in Four Legal Jurisdictions.

Dementia is associated with the gradual impairment of mental ability. The population of people suffering from dementia is as large as 50 million. Most dementia cases result from various neurodegenerative diseases (NDs) linked by a progressive degeneration of neurons. Among NDs, Alzheimer's disease (AD) is the most frequent cause of dementia and accounts for 60- 80% of cases. Certain pathological changes on the cellular and subcellular level occur even 15 years before the manifestation of clinical symptoms of AD. This first asymptomatic phase of AD is considered a preclinical stage, whereas mild cognitive impairment (MCI) is the symptomatic pre-dementia stage. The third, fully symptomatic phase of AD is dementia due to AD. The presence of specific proteins in the cerebrospinal fluid (CSF) may be considered as a characteristic feature of some NDs. The measurement of their CSF concentrations, together with neuropsychological examination and neuroimaging, may be useful for diagnosing AD. The collection of CSF samples is performed by lumbar puncture, which is a medical procedure that requires obtaining informed consent from patients. While asymptomatic AD patients have full legal capacity, those with dementia require a legal guardian who will represent them. Thus, the objective of this study is to compare the legal systems regulating the legal capacity issue in the USA, U.K. (England and Wales), Germany, and Poland. These countries have been chosen as examples of three different types of legal orders, according to the sources of law, i.e., civil law, common law, and case law.

Examination of Alzheimer's disease by a combination of electrostatic force and mechanical measurement.

Alzheimer's disease (AD) is the most common dementia and neurodegenerative disorder disease in central nervous system, and threatens the people's health seriously. But till now there are no effective ways to diagnose and treat AD. Herein, the differences between charge propagation, surface morphology, and Young's modulus of the hippocampus, in healthy and AD mice have been investigated using advanced modes of Atomic Force Microscopy (AFM). The ability of charge transfer in AD samples has decreased compared with healthy samples. There are compact layered structures in hippocampus from healthy sample, whereas there are no obvious layered structures in hippocampus from AD sample. The Young's modulus of hippocampus from AD sample is about half of that from healthy sample. The results demonstrate that AFM will be helpful in the further study of the functions of hippocampus and pathogenyof AD. LAY DESCRIPTION: Alzheimer's disease is the most common cause of dementia, a neurodegenerative disease which especially affects elderly people, threatens people's health seriously. The pathological features of AD are senile plaques, neurofibrillary tangles, and cerebral atrophy. The main clinical symptoms of AD are progressive memory impairment, cognitive dysfunction, and loss of language skills, as there are disorder in limbic and cortices. The morbidity rate increases with age and is currently at 5% and 20% among people older than 65 and 85, respectively. Thus AD has a heavy socioeconomic burden, especially in an aging society. So far, there are no effective therapeutic clinical treatments, and no effective means and methods to test and diagnose early stage AD. This means that further studies are essential to gain a deeper, fundamental understanding of the pathogenesis of AD. In this work, the surface morphology, electrical and mechanical properties of the hippocampi from healthy and AD mice have been investigated by Atomic Force Microscopy (AFM) at nanometre scale for the first time. The hippocampi from healthy mice are composed of compact layered structures, whereas there are no obvious characteristic features in the hippocampi from AD mice. The electrical properties of hippocampus slices were studied by the Electrostatic Force Microscopy (EFM) mode of AFM. The charge propagation ability of axons from AD mice has decreased dramatically compared to that of healthy mice. After charge injection (injection voltage was +10 V) the charge density was 2.3 × 105 Cμm-2 in healthy samples, which was larger than that from the AD samples (1.0 × 105 Cμm-2 ). The Young's modulus of hippocampi from healthy and AD mice were 104.0 and 40.1 kPa, respectively, as revealed by the quantitative nanomechanical mapping (QNM) mode of AFM. It indicates that when AD occurs, the Young's modulus will be lower than the healthy sample. These observations and experimental approaches will be useful in future studies of the pathogeny of AD.

Prediction of Autopsy Verified Neuropathological Change of Alzheimer's Disease Using Machine Learning and MRI.

Background: Alzheimer’s disease (AD) is the most common form of dementia. While neuropathological changes pathognomonic for AD have been defined, early detection of AD prior to cognitive impairment in the clinical setting is still lacking. Pioneer studies applying machine learning to magnetic-resonance imaging (MRI) data to predict mild cognitive impairment (MCI) or AD have yielded high accuracies, however, an algorithm predicting neuropathological change is still lacking. The objective of this study was to compute a prediction model supporting a more distinct diagnostic criterium for AD compared to clinical presentation, allowing identification of hallmark changes even before symptoms occur.Methods: Autopsy verified neuropathological changes attributed to AD, as described by a combined score for Aβ-peptides, neurofibrillary tangles and neuritic plaques issued by the National Institute on Aging – Alzheimer’s Association (NIAA), the ABC score for AD, were predicted from structural MRI data with RandomForest (RF). MRI scans were performed at least 2 years prior to death. All subjects derive from the prospective Vienna Trans-Danube Aging (VITA) study that targeted all 1750 inhabitants of the age of 75 in the starting year of 2000 in two districts of Vienna and included irregular follow-ups until death, irrespective of clinical symptoms or diagnoses. For 68 subjects MRI as well as neuropathological data were available and 49 subjects (mean age at death: 82.8 ± 2.9, 29 female) with sufficient MRI data quality were enrolled for further statistical analysis using nested cross-validation (CV). The decoding data of the inner loop was used for variable selection and parameter optimization with a fivefold CV design, the new data of the outer loop was used for model validation with optimal settings in a fivefold CV design. The whole procedure was performed ten times and average accuracies with standard deviations were reported.Results: The most informative ROIs included caudal and rostral anterior cingulate gyrus, entorhinal, fusiform and insular cortex and the subcortical ROIs anterior corpus callosum and the left vessel, a ROI comprising lacunar alterations in inferior putamen and pallidum. The resulting prediction models achieved an average accuracy for a three leveled NIAA AD score of 0.62 within the decoding sets and of 0.61 for validation sets. Higher accuracies of 0.77 for both sets, respectively, were achieved when predicting presence or absence of neuropathological change.Conclusion: Computer-aided prediction of neuropathological change according to the categorical NIAA score in AD, that currently can only be assessed post-mortem, may facilitate a more distinct and definite categorization of AD dementia. Reliable detection of neuropathological hallmarks of AD would enable risk stratification at an earlier level than prediction of MCI or clinical AD symptoms and advance precision medicine in neuropsychiatry.