Synopsis on the Linkage of Alzheimer's and Parkinson's Disease with Chronic Diseases

Neurodegeneration is the progressive loss of neuronal structure and function, which ultimately leads to neurological disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis, and Huntington's disease. Even after the recent significant advances in neurobiology, the above‐mentioned disorders continue to haunt the global population. Several studies have suggested the role of specific environmental and genetic risk factors associated with these disorders. However, the exact mechanism associated with the progression of these disorders still needs to be elucidated. In the recent years, sophisticated research has revealed interesting association of prominent neurodegenerative disorders such as AD and PD with chronic diseases such as cancer, diabetes, and cardiovascular diseases. Several common molecular mechanisms such as generation of free radicals, oxidative DNA damage, aberrations in mitochondrial DNA, and dysregulation of apoptosis have been highlighted as possible points of connection. The present review summarizes the possible mechanism of coexistence of AD and PD with other chronic diseases.     

Neural stem cell‐based treatment for neurodegenerative diseases

Human neurodegenrative diseases such as Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD) are caused by a loss of neurons and glia in the brain or spinal cord. Neurons and glial cells have successfully been generated from stem cells such as embryonic stem cells (ESCs), mesenchymal stem cells (MSCs) and neural stem cells (NSCs), and stem cell‐based cell therapies for neurodegenerative diseases have been developed. A recent advance in generatioin of a new class of pluripotent stem cells, induced pluripotent stem cells (iPSCs), derived from patients' own skin fibroblasts, opens doors for a totally new field of personalized medicine. Transplantation of NSCs, neurons or glia generated from stem cells in animal models of neurodegenrative diseases, including PD, HD, ALS and AD, demonstrates clinical improvement and also life extension of these animals. Additional therapeutic benefits in these animals can be provided by stem cell‐mediated gene transfer of therapeutic genes such as neurotrophic factors and enzymes. Although further research is still needed, cell and gene therapy based on stem cells, particularly using neurons and glia derived from iPSCs, ESCs or NSCs, will become a routine treatment for patients suffering from neurodegenerative diseases and also stroke and spinal cord injury.     

Neuropsychiatric symptoms associated multimodal brain networks in Alzheimer's disease

Concomitant neuropsychiatric symptoms (NPS) are associated with accelerated Alzheimer's disease (AD) progression. Identifying multimodal brain imaging patterns associated with NPS may help understand pathophysiology correlates AD. Based on the AD continuum, a supervised learning strategy was used to guide four-way multimodal neuroimaging fusion (Amyloid, Tau, gray matter volume, brain function) by using NPS total score as the reference. Loadings of the identified multimodal patterns were compared across the AD continuum. Then, regression analyses were performed to investigate its predictability of longitudinal cognition performance. Furthermore, the fusion analysis was repeated in the four NPS subsyndromes. Here, an NPS-associated pathological–structural–functional covaried pattern was observed in the frontal-subcortical limbic circuit, occipital, and sensor-motor region. Loading of this multimodal pattern showed a progressive increase with the development of AD. The pattern significantly correlates with multiple cognitive domains and could also predict longitudinal cognitive decline. Notably, repeated fusion analysis using subsyndromes as references identified similar patterns with some unique variations associated with different syndromes. Conclusively, NPS was associated with a multimodal imaging pattern involving complex neuropathologies, which could effectively predict longitudinal cognitive decline. These results highlight the possible neural substrate of NPS in AD, which may provide guidance for clinical management.     

Protective Effects of Physical Exercise in Alzheimer's Disease and Parkinson's Disease: A Narrative Review

Alzheimer''s disease (AD) and Parkinson''s disease (PD) are devastating, frequent, and still incurable neurodegenerative diseases that manifest as cognitive and motor disorders. Epidemiological data support an inverse relationship between the amount of physical activity (PA) undertaken and the risk of developing these two diseases. Beyond this preventive role, exercise may also slow down their progression. Several mechanisms have been suggested for explaining the benefits of PA in the prevention of AD. Aerobic physical exercise (PE) activates the release of neurotrophic factors and promotes angiogenesis, thereby facilitating neurogenesis and synaptogenesis, which in turn improve memory and cognitive functions. Research has shown that the neuroprotective mechanisms induced by PE are linked to an increased production of superoxide dismutase, endothelial nitric oxide synthase, brain-derived neurotrophic factor, nerve growth factor, insulin-like growth factor, and vascular endothelial growth factor, and a reduction in the production of free radicals in brain areas such as the hippocampus, which is particularly involved in memory. Other mechanisms have also been reported in the prevention of PD. Exercise limits the alteration in dopaminergic neurons in the substantia nigra and contributes to optimal functioning of the basal ganglia involved in motor commands and control by adaptive mechanisms involving dopamine and glutamate neurotransmission. AD and PD are expansive throughout our ageing society, and so even a small impact of nonpharmacological interventions, such as PA and exercise, may have a major impact on public health.     

Neuroimaging of Parkinson's disease: Expanding views

Advances in molecular and structural and functional neuroimaging are rapidly expanding the complexity of neurobiological understanding of Parkinson's disease (PD). This review article begins with an introduction to PD neurobiology as a foundation for interpreting neuroimaging findings that may further lead to more integrated and comprehensive understanding of PD. Diverse areas of PD neuroimaging are then reviewed and summarized, including positron emission tomography, single photon emission computed tomography, magnetic resonance spectroscopy and imaging, transcranial sonography, magnetoencephalography, and multimodal imaging, with focus on human studies published over the last five years. These included studies on differential diagnosis, co-morbidity, genetic and prodromal PD, and treatments from l-DOPA to brain stimulation approaches, transplantation and gene therapies. Overall, neuroimaging has shown that PD is a neurodegenerative disorder involving many neurotransmitters, brain regions, structural and functional connections, and neurocognitive systems. A broad neurobiological understanding of PD will be essential for translational efforts to develop better treatments and preventive strategies. Many questions remain and we conclude with some suggestions for future directions of neuroimaging of PD.     

Mirror neurons and their relationship with neurodegenerative disorders

The finding of mirror neurons (MNs) has provided a biological substrate to a new concept of cognition, relating data on actions and perceptions not only to integrate perception in action planning and execution but also as a neural mechanism supporting a wide range of cognitive functions. Here we first summarize data on MN localization and role in primates, then we report findings in normal human subjects: functional magnetic resonance imaging and neurophysiological studies sustain that MNs have a role in motor learning and recognizing actions and intentions of others, and they also support an embodied view of language, empathy, and memory. Then, we detail the results of literature searching on MNs and embodied cognition in Parkinson's disease (PD), frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS), and in mild cognitive impairment (MCI)/Alzheimer's disease (AD). In PD the network of MN could be altered, but its hyperactivation might support motor and cognitive performances at least in early stages. In the ALS/FTD continuum, preliminary evidence points out to an involvement of the MN network, which could explain language and inter-subjectivity deficits shown in patients affected by these clinical entities. In the MCI/AD spectrum, a few recent studies suggest a possible progressive involvement from posterior to anterior areas of the MN network, with the brain putting in place compensatory mechanisms in early stages. Reinterpreting neurodegenerative diseases at the light of the new views about brain organization stemming from the discovery of MN could help to better comprehend clinical manifestations and open new pathways to rehabilitation.     

The effect of drug treatment on neurogenesis in Parkinson's disease

There has been recent interest in the possibility that impaired neurogenesis may contribute to the decline in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease (PD). We have investigated the effects of commonly used treatments for PD on neural stem cell (NSC) activity in nondemented patients. Postmortem of brain tissue containing the subventricular zone (SVZ) and ependymal layer cells was obtained from 32 nondemented patients with PD. NSC activity was assessed by immunohistochemical staining for RNA‐binding protein Musashi1. Regression analyses were then used to identify which clinical factors independently influenced NSC activity. Disease duration was negatively associated with SVZ Musashi1 staining, whereas lifetime levodopa was positively associated in this region. Our findings suggest a positive impact of chronic L ‐dopa use on the number of NSC in the SVZ of PD patients, which may have relevance for future studies on neuroprotection in neurodegenerative diseases. © 2010 Movement Disorder Society.     

An overview of circulating cell-free microRNAs as putative biomarkers in Alzheimer's and Parkinson's Diseases

Circulating cell-free microRNAs (miRNAs) are stable in many biological fluids and their expression profiles can suffer changes under different physiological and pathological conditions. In the last few years, miRNAs have been proposed as putative noninvasive biomarkers in diagnosis, prognosis and response to treatment for several diseases, including neurodegenerative disorders as Alzheimer's disease (AD) and Parkinson's disease (PD). Cognitive and/or motor impairments are usually considered for establishing clinical diagnosis, and at this stage, the majority of the neurons may already be lost making difficult attempts of novel therapies. In this review, we intend to survey the circulating cell-free miRNAs found as dysregulated in cerebrospinal fluid, serum and plasma samples in AD and PD patients, and show how those miRNAs can be useful for early and differential diagnosis. Beyond that, we highlighted the miRNAs that are possibly related to common molecular mechanisms in the neurodegeneration process, as well those miRNAs related to specific disease pathways.     

Recurrent systemic infections with Streptococcus pneumoniae do not aggravate the course of experimental neurodegenerative diseases

Neurological symptoms of patients suffering from neurodegenerative diseases such as Alzheimer's dementia (AD), Parkinson's disease (PD), or amyotrophic lateral sclerosis (ALS) often worsen during infections. We assessed the disease‐modulating effects of recurrent systemic infections with the most frequent respiratory pathogen, Streptococcus pneumoniae, on the course of AD, PD, and ALS in mouse models of these neurodegenerative diseases [transgenic Tg2576 mice, (Thy1)‐[A30P]αSYN mice, and Tg(SOD1‐G93A) mice]. Mice were repeatedly challenged intraperitoneally with live S. pneumoniae type 3 and treated with ceftriaxone for 3 days. Infection caused an increase of interleukin‐6 concentrations in brain homogenates. The clinical status of (Thy1)‐[A30P]αSYN mice and Tg(SOD1‐G93A) mice was monitored by repeated assessment with a clinical score. Motor performance was controlled by the tightrope test and the rotarod test. In Tg2576 mice, spatial memory and learning deficits were assessed in the Morris water maze. In none of the three mouse models onset or course of the disease as evaluated by the clinical tests was affected by the recurrent systemic infections performed. Levels of α‐synuclein in brains of (Thy1)‐[A30P]αSYN mice did not differ between infected animals and control animals. Plaque sizes and concentrations of Aβ 1–40 and Aβ 1–42 were not significantly different in brains of infected and uninfected Tg2576 mice. In conclusion, onset and course of disease in mouse models of three common neurodegenerative disorders were not influenced by repeated systemic infections with S. pneumoniae, indicating that the effect of moderately severe acute infections on the course of neurodegenerative diseases may be less pronounced than suspected. © 2009 Wiley‐Liss, Inc.     

Review: Somatic mutations in neurodegeneration

Somatic mutations are postzygotic mutations which may lead to mosaicism, the presence of cells with genetic differences in an organism. Their role in cancer is well established, but detailed investigation in health and other diseases has only been recently possible. This has been empowered by the improvements of sequencing techniques, including single‐cell sequencing, which can still be error‐prone but is rapidly improving. Mosaicism appears relatively common in the human body, including the normal brain, probably arising in early development, but also potentially during ageing. In this review, we first discuss theoretical considerations and current evidence relevant to somatic mutations in the brain. We present a framework to explain how they may be integrated with current views on neurodegeneration, focusing mainly on sporadic late‐onset neurodegenerative diseases (Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis). We review the relevant studies so far, with the first evidence emerging in Alzheimer's in particular. We also discuss the role of mosaicism in inherited neurodegenerative disorders, particularly somatic instability of tandem repeats. We summarize existing views and data to present a model whereby the time of origin and spatial distribution of relevant somatic mutations, combined with any additional risk factors, may partly determine the development and onset age of sporadic neurodegenerative diseases.     

Invited Review: From nose to gut – the role of the microbiome in neurological disease

Inflammation and neurodegeneration are key features of many chronic neurological diseases, yet the causative mechanisms underlying these processes are poorly understood. There has been mounting interest in the role of the human microbiome in modulating the inflammatory milieu of the central nervous system (CNS) in health and disease. To date, most research has focussed on a gut‐brain axis, with other mucosal surfaces being relatively neglected. We herein take the novel approach of comprehensively reviewing the roles of the microbiome across several key mucosal interfaces – the nose, mouth, lung and gut – in health and in Parkinson's disease (PD), Alzheimer's disease (AD) and multiple sclerosis (MS). This review systematically appraises the anatomical and microbiological landscape of each mucosal surface in health and disease before considering relevant mechanisms that may influence the initiation and progression of PD, AD and MS. The cumulative effects of dysbiosis from the nose to the gut may contribute significantly to neurological disease through a wide variety of mechanisms, including direct translocation of bacteria and their products, and modulation of systemic or CNS‐specific immunity. This remains an understudied and exciting area for future research and may lead to the development of therapeutic targets for chronic neurological disease.     

Development of stem cell-based therapies for Parkinson's disease

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons of the substantia nigra pars compacta in the brain with an unknown cause. Current pharmacological treatments for PD are only symptomatic and there is still no cure for this disease nowadays. In fact, transplantation of human fetal ventral midbrain cells into PD brains has provided a proof of concept that cell replacement therapy can be used for some PD patients, beneficial for improving their symptoms. However, the ethical and practical issues of human fetal tissue will inevitably limit its widespread clinical use. Therefore, it is essential to find alternative cell sources for the future cell transplantation for PD patients. With recent development in stem cell technology, here, we review the different types of stem cells and their main properties currently explored, which could be developed as a possible cell therapy for PD treatment.     

Three Large-Scale Functional Brain Networks from Resting-State Functional MRI in Subjects with Different Levels of Cognitive Impairment

Normal aging and to a greater degree degenerative brain diseases such as Alzheimer''s disease (AD), cause changes in the brain''s structure and function. Degenerative changes in brain structure and decline in its function are associated with declines in cognitive ability. Early detection of AD is a key priority in dementia services and research. However, depending on the disease progression, neurodegenerative manifestations, such as cerebral atrophy, are detected late in course of AD. Functional changes in the brain may be an indirect indicator of trans-synaptic activity and they usually appear prior to structural changes in AD. Resting-state functional magnetic resonance imaging (RS-fMRI) has recently been highlighted as a new technique for interrogating intrinsic functional connectivity networks. Among the majority of RS-fMRI studies, the default mode network (DMN), salience network (SN), and central executive network (CEN) gained particular focus because alterations to their functional connectivity were observed in subjects who had AD, who had mild cognitive impairment (MCI), or who were at high risk for AD. Herein, we present a review of the current research on changes in functional connectivity, as measured by RS-fMRI. We focus on the DMN, SN, and CEN to describe RS-fMRI results from three groups: normal healthy aging, MCI and AD.     

Applications of amyloid,tau, and neuroinflammation PET imaging to Alzheimer's disease and mild cognitive impairment

Alzheimer's disease (AD) is a devastating and progressive neurodegenerative disease for which there is no cure. Mild cognitive impairment (MCI) is considered a prodromal stage of the disease. Molecular imaging with positron emission tomography (PET) allows for the in vivo visualisation and tracking of pathophysiological changes in AD and MCI. PET is a very promising methodology for differential diagnosis and novel targets of PET imaging might also serve as biomarkers for disease‐modifying therapeutic interventions. This review provides an overview of the current status and applications of in vivo molecular imaging of AD pathology, specifically amyloid, tau, and microglial activation. PET imaging studies were included and evaluated as potential biomarkers and for monitoring disease progression. Although the majority of radiotracers showed the ability to discriminate AD and MCI patients from healthy controls, they had various limitations that prevent the recommendation of a single technique or tracer as an optimal biomarker. Newer research examining amyloid, tau, and microglial PET imaging in combination suggest an alternative approach in studying the disease process.     

Position Emission Tomography/Single‐Photon Emission Tomography Neuroimaging for Detection of Premotor Parkinson's Disease

Premotor Parkinson's disease (PD) refers to a prodromal stage of Parkinson's disease (PD) during which nonmotor clinical features may be present. Currently, it is difficult to make an early diagnosis for premotor PD. Molecular imaging with position emission tomography (PET) or single‐photon emission tomography (SPECT) offers a wide variety of tools for overcoming this difficulty. Indeed, molecular imaging techniques may play a crucial role in diagnosing, monitoring and evaluating the individuals with the risk for PD. For example, dopaminergic dysfunctions can be identified by detecting the expression of vesicular monoamine transporter (VMAT2) and aromatic amino acid decarboxylase (AADC) to evaluate the conditions of dopaminergic terminals functions in high‐risk individuals of PD. This detection provides a sensitive and specific measurement of nonmotor symptoms (NMS) such as olfactory dysfunction, sleep disorders, and psychiatric symptoms in the high‐risk patients, especially at the premotor phase. Molecular imaging technique is capable of detecting the dysfunction of serotonergic, noradrenergic, and cholinergic systems that are typically associated with premotor manifestations. This review discusses the importance of SPECT/PET applications in the detection of premotor markers preceding motor abnormalities with highlighting their great potential for early and accurate diagnosis of premotor symptoms of PD and its scientific significance.     

Differentiation of claustrum resting‐state functional connectivity in healthy aging,Alzheimer's disease,and Parkinson's disease

The claustrum is a sheet‐like of telencephalic gray matter structure whose function is poorly understood. The claustrum is considered a multimodal computing network due to its reciprocal connections with almost all cortical areas as well as subcortical structures. Although the claustrum has been involved in several neurodegenerative diseases, specific changes in connections of the claustrum remain unclear in Alzheimer''s disease (AD), and Parkinson''s disease (PD). Resting‐state fMRI and T1‐weighted structural 3D images from healthy elderly (n = 15), AD (n = 16), and PD (n = 12) subjects were analyzed. Seed‐based FC analysis was performed using CONN FC toolbox and T1‐weighted images were analyzed with the Computational Anatomy Toolbox for voxel‐based morphometry analysis. While we observed a decreased FC between the left claustrum and sensorimotor cortex, auditory association cortex, and cortical regions associated with social cognition in PD compared with the healthy control group (HC), no significant difference was found in alterations in the FC of both claustrum comparing the HC and AD groups. In the AD group, high FC of claustrum with regions of sensorimotor cortex and cortical regions related to cognitive control, including cingulate gyrus, supramarginal gyrus, and insular cortex were demonstrated. In addition, the structural results show significantly decreased volume in bilateral claustrum in AD and PD compared with HC. There were no significant differences in the claustrum volumes between PD and AD groups so the FC may offer more precise findings in distinguishing changes for claustrum in AD and PD.     

Neuropsychiatric symptoms in Parkinson's disease: Fronto-striatal atrophy contributions

BackgroundNeuropsychiatric symptoms (NPS) in Parkinson's disease (PD) have been mostly attributed to neurotransmitter imbalances. However, recent findings suggest that gray matter atrophy also contributes to NPS in PD. We contrast PD patients with different levels of NPS, who are well-matched for dopaminergic medication levels and disease stage, to identify the fronto-striatal gray matter atrophy areas associated with NPS in PD.MethodsFifty mild, non-demented PD patients were included. We median-split the group via a neuropsychiatric screening tool (Cambridge Behavioural Inventory-Revised), which resulted in higher vs. lower NPS groups (n = 25 in each group). Using T1 brain scans acquired on a 3 Tesla MRI scanner, voxel-based morphometry analysis was applied to characterize the pattern of fronto-striatal gray matter atrophy associated with elevated NPS.ResultsWe found that the higher NPS group was characterized by greater atrophy in the prefrontal cortex, but not striatal areas. This was further corroborated by a post-hoc analysis cross-correlating the severity of NPS with gray matter loss across the whole PD group, which revealed that atrophy in the orbitofrontal cortex and frontal pole was specifically associated with elevated NPS.ConclusionsPrefrontal cortex atrophy in PD has an additional effect to dopamine replacement therapy on the generation of NPS in these patients. These findings are an important step towards the delineation of atrophy vs. neurochemical imbalance in PD, and the results emphasize the importance of considering interactions between prefrontal atrophy and neurochemical dysfunction in the genesis of neuropsychiatric symptoms in PD.     

Olfactory dysfunctions in neurodegenerative disorders

Olfactory dysfunction is a common symptom in the patients with neurodegenerative disorders, particularly in Parkinson's disease (PD) and Alzheimer's disease (AD). Recently, studies of olfactory dysfunction have focused on its potential as a medication-independent biomarker for disease progression and as an early indicator for the diagnosis of neurodegenerative disorders. In the past decades, great achievements have been obtained in elucidating the neuroanatomy and the function of olfactory system, yet the pathogenesis of olfactory dysfunction in neurodegenerative disorders remains elusive. The neuropathologic changes of olfactory dysfunction in neurodegenerative diseases may involve the olfactory epithelium, olfactory bulb, primary olfactory cortices, and their secondary targets changes. This article summarizes the up-to-date knowledge on pathophysiological changes of the olfactory system in neurodegenerative disorders and attempts to find the association between olfactory dysfunction and neurodegenerative disorders.     

早发性与晚发性阿尔茨海默病的多模态影像学研究进展

阿尔茨海默病（AD）是最常见的神经系统退行性疾病,其特征是以记忆为主的进行性认知功能损害。根据发病年龄可分为早发性AD（EOAD）和晚发性AD（LOAD）,二者在临床进程和神经病理学方面存在差异。近年来,多种影像学技术和新型示踪剂的开发促进了AD影像学生物标志物的出现,为深入了解EOAD和LOAD的影像学特征提供了依据。该文旨在对EOAD和LOAD的磁共振成像、单光子发射计算机断层扫描、正电子发射断层扫描的多模态影像学研究进展进行总结,探讨两种类型AD的影像学特征与区别。