Progression Of Neurodegenerative Process Research Articles

The contribution of white matter lesions (WML) to Parkinson's disease cognitive impairment symptoms: A critical review of the literature

We reviewed the impact of white matter lesions (WML) of cerebrovascular origin on cognitive impairment in Parkinson's disease (PD) patients. A search of PUBMED and Googlescholar.com revealed eleven studies that met the inclusion criteria: diagnosis based on the United Kingdom Brain Bank criteria (UK BBC); cognitive assessment; WML assessed on magnetic resonance imaging (MRI) by semiquantitative visual scales or automated method.Eight studies described the negative impact of WML on cognition in PD. Patients with mild cognitive impairment (MCI) and dementia had significantly more WML than the group without MCI and dementia. There was significant relationship between increasing total WML volume and worse performance on executive function, memory and language. Patients with vascular parkinsonism and dopaminergic denervation had more severe frontal lobe dysfunctions than patients with PD. In contrast in three studies there was no negative correlation between WML and cognition. Although the progression of neurodegenerative process in advanced stage of PD has been recognized as being mainly responsible for cognitive impairment in PD, WML may also be a contributing factor. It is possible that by reducing the vascular risk factors that cause WML cognitive impairment could be prevented or slowed down.

Fyn Kinase Regulates Microglial Neuroinflammatory Responses in Cell Culture and Animal Models of Parkinson's Disease.

Parkinson's disease (PD) is a complex multifactorial disease characterized by the progressive loss of midbrain dopamine neurons. Sustained microglia-mediated neuroinflammation has been recognized as a major pathophysiological contributor to chronic degenerative processes in PD; however, the key molecular signaling mechanisms underlying microglial activation are not entirely clear. Herein, we identified a novel role for the non-receptor tyrosine kinase Fyn in regulating neuroinflammatory responses in microglia. Our data clearly suggest that the Fyn-PKCδ signaling axis acts as a major upstream signaling mediator of the sustained neuroinflammatory processes in cell culture and animal models of PD. Our finding has important clinical significance to PD because it identifies Fyn as a potential translational target for intervention of progressive neurodegenerative processes in PD.

Tratamiento de la enfermedad de Alzheimer

Alzheimer's disease (AD) is a chronic progressive neurodegenerative process that involves considerable suffering. The etiopathogenic context is complex and the physical and social environments are usually fragile, so all therapeutic efforts must be framed to slowing down the course of the disease and improve quality of life (QoL). Care is based on the treatment of medical comorbidity, prevention and management of psychological and behavioral problems, specific the pharmacological treatment and information, advice and ongoing support for both the patient and caregiver. Cholinesterase inhibitor drugs (ICE) and memantine delay cognitive decline and improve apathy and psychotic symptoms. Non-pharmacological therapies provide additional and complementary benefits in areas where drugs are usually less effective (emotions, behavior and QoL). There are several lines of pharmacological research for AD that could delay the onset of dementia or prolong the milder stages of the disease.

Protective Effect of Centella asiatica against Aluminium-Induced Neurotoxicity in Cerebral Cortex, Striatum, Hypothalamus and Hippocampus of Rat Brain- Histopathological, and Biochemical Approach

Aluminum (Al) is a potent environmental neurotoxin, which is involved in the progression of neurodegenerative processes. Remarkable biological and medicinal properties of Centella asiatica (CA) are well known in last few decades. Therefore, the present study has been designed to explore the neuroprotective effect of CA on chronic aluminium chloride (AlCl3) exposure induced neurotoxicity in rat brain regions (cerebral cortex, striatum, hypothalamus and hippocampus). Wistar albino rats were segregated into four groups: group 1-control rats, group 2- rats received AlCl3 (300 mg/kg body weight, every day orally) for 60 days, rats in group 3-received CA (500 mg/kg body weight, orally) and group 4 rats were initiated with both AlCl3 and CA treatment. Administration of AlCl3 developed behavioral deficits, triggered lipid peroxidation (LPO), compromised acetylcholine esterase (AChE) activity, and reduced the levels of superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH) and glutathione-S-transferase (GST) and caused histologic aberrations. AlCl3–induced alterations in the activities of SOD, CAT, GSH and GST, levels of LPO, activity of AChE, behavioral deficits and histologic aberrations were attenuated on treatment with CA. Results of the study demonstrate neuroprotective potential of CA against AlCl3- induced oxidative damage and cognitive dysfunction.

Radiological Imaging in Ataxia Telangiectasia: a Review

The human genetic disorder ataxia telangiectasia (A-T) is characterised by neurodegeneration, immunodeficiency, radiosensitivity, cell cycle checkpoint defects, genomic instability and cancer predisposition. Progressive cerebellar ataxia represents the most debilitating aspect of this disorder. At present, there is no therapy available to cure or prevent the progressive symptoms of A-T. While it is possible to alleviate some of the symptoms associated with immunodeficiency and deficient lung function, neither the predisposition to cancer nor the progressive neurodegeneration can be prevented. Significant effort has focused on improving our understanding of various clinical, genetic and immunological aspects of A-T; however, little attention has been directed towards identifying altered brain structure and function using MRI. To date, most imaging studies have reported radiological anomalies in A-T. This review outlines the clinical and biological features of A-T along with known radiological imaging anomalies. In addition, we briefly discuss the advent of high-resolution MRI in conjunction with diffusion-weighted imaging, which enables improved investigation of the microstructural tissue environment, giving insight into the loss in integrity of motor networks due to abnormal neurodevelopmental or progressive neurodegenerative processes. Such imaging approaches have yet to be applied in the study of A-T and could provide important new information regarding the relationship between mutation of the ataxia telangiectasia mutated (ATM) gene and the integrity of motor circuitry.

Further evidence about the crucial role of CSF biomarkers in diagnosis of posterior cortical atrophy

Cerebrospinal fluid (CSF) biomarkers (protein tau, phosphorylated tau and amyloid Beta 1-42) are recognized as a supportive feature in diagnosis of Alzheimer's disease (AD) and their role in identifying atypical variants of AD is currently under investigation. We dosed these proteins in nine patients clinically and instrumentally affected by posterior cortical atrophy (PCA), a rare disorder characterized by a progressive neurodegenerative process that involves primarily the posterior brain regions. We compared the obtained values with a large group of AD patients (N = 117), recruited in our neurological department. Our data revealed no differences in the CSF profile between PCA and AD, showing abnormal values of protein tau, phosphorylated tau and amyloid Beta 1-42 in both groups of patients. This study underlines the diagnostic importance of CSF biomarkers in PCA patients, supporting the hypothesis that PCA is an atypical variant of AD with an onset before the age of 65.

Alzheimer disease: sleep, orexin and cognitive decline

Introduction In Alzheimer’s disease (AD) several networks including regions regulating the sleep-wake rhythm are altered. Orexin-A is an hypothalamic neuropeptide contributing to the regulation of the sleep-wake cycle. The aim of our study was to investigate the possible involvement of the orexinergic system in the AD neurodegenerative processes and its relationship with sleep impairment. Materials and methods We included 48 consecutive untreated AD patients and 29 healthy controls. Based on MMSE, AD patients were divided in 2 groups: mild AD (MMSE ⩾ 21; 21 subjects) and moderate-severe AD (MMSE 21; 27 subjects). We quantified orexin CSF levels in AD patients and controls, and examined potential links to the established AD markers CSF levels, as tau, phospho-tau (ptau), and beta-amyloid1–42 (A β 1–42). Moreover, AD patients underwent a full nocturnal polysomnography (PSG). Finally, CSF results were correlated with sleep structure parameters and MMSE. Results Regarding CSF data, control subjects showed orexin CSF levels not significantly different with AD patients as well as with mild AD subjects. However, moderate-severe AD patients showed increased orexin CSF levels in respect to both mild AD patients and controls. Regarding PSG parameters, moderate–severe AD patients, compared to mild AD subjects, showed a significant reduction in sleep efficiency (SE) and a significant increase in wakefulness after sleep onset (WASO) and in REM latency. Moreover, in AD patients the orexin CSF levels were negatively correlated with REM sleep, slow wave sleep (SWS) and SE, whereas were positively correlated with WASO and sleep latency. Furthermore, it appeared to exist a positive correlation between the increase of orexin and tau CSF levels in AD patients. A β 1–42 CSF levels were negatively correlated with WASO whereas were positively correlated with REM sleep. Tau CSF levels were negatively correlated with SWS. The decrease of MMSE correlated with the impairment of SE and REM sleep and the increase of WASO. Conclusion Our study shows that in AD cognitive decline is linked to a parallel sleep deterioration, which appears to be related to an increase of the CSF orexin levels. In conclusion, our results demonstrate that the orexinergic system is not impaired in AD, but its output and function appears to be overexpressed along the progression of neurodegenerative processes, possibly due to an unbalance of the neurotransmitters networks regulating the wake-sleep cycle towards the systems promoting wakefulness. Acknowledgements We are grateful to Ms. Alessandra Nitti for technical support, Dr. Francesca Izzi for acquisition of data, Prof. Nicola Biagio Mercuri for study supervision and Prof. Giuseppe Sancesario and Dr. Alessandro Martorana for acquisition of data and study supervision.

IFN-γ Production by Amyloid β–Specific Th1 Cells Promotes Microglial Activation and Increases Plaque Burden in a Mouse Model of Alzheimer’s Disease

Alzheimer's disease (AD) is characterized by the presence of amyloid-β (Aβ)-containing plaques, neurofibrillary tangles, and neuronal loss in the brain. Inflammatory changes, typified by activated microglia, particularly adjacent to Aβ plaques, are also a characteristic of the disease, but it is unclear whether these contribute to the pathogenesis of AD or are a consequence of the progressive neurodegenerative processes. Furthermore, the factors that drive the inflammation and neurodegeneration remain poorly understood. CNS-infiltrating T cells play a pivotal role in the pathogenesis of multiple sclerosis, but their role in the progression of AD is still unclear. In this study, we examined the role of Aβ-specific T cells on Aβ accumulation in transgenic mice that overexpress amyloid precursor protein and presenilin 1 (APP/PS1). We found significant infiltration of T cells in the brains of APP/PS1 mice, and a proportion of these cells secreted IFN-γ or IL-17. Aβ-specific CD4 T cells generated by immunization with Aβ and a TLR agonist and polarized in vitro to Th1-, Th2-, or IL-17-producing CD4(+) T cells, were adoptively transferred to APP/PS1 mice at 6 to 7 mo of age. Assessment of animals 5 wk later revealed that Th1 cells, but not Th2 or IL-17-producing CD4(+) T cells, increased microglial activation and Aβ deposition, and that these changes were associated with impaired cognitive function. The effects of Th1 cells were attenuated by treatment of the APP/PS1 mice with an anti-IFN-γ Ab. Our study suggests that release of IFN-γ from infiltrating Th1 cells significantly accelerates markers of diseases in an animal model of AD.

Traumatic Brain Injury as a Chronic Health Condition

Growing evidence indicates that multiple types of brain injury, including traumatic brain injury, are dynamic conditions that continue to change years after onset. For a subset of individuals who incur these injuries, decline occurs over time and is likely due to progressive neurodegenerative processes, comorbid conditions, aging, behavioral choices, and/or psychosocial factors. Deterioration, whether directly or indirectly associated with the original brain injury, necessitates a clinical approach as a chronic health condition, including identification of risk and protective factors, protocols for early identification, evidence-based preventive and ameliorative treatment, and training in self-management. We propose that the acknowledgment of chronic brain injury will facilitate the research necessary to provide a disease management approach.

Early Alzheimer's and Parkinson's disease pathology in urban children: Friend versus Foe responses--it is time to face the evidence.

Chronic exposure to particulate matter air pollution is known to cause inflammation leading to respiratory- and cardiovascular-related sickness and death. Mexico City Metropolitan Area children exhibit an early brain imbalance in genes involved in oxidative stress, inflammation, and innate and adaptive immune responses. Early dysregulated neuroinflammation, brain microvascular damage, production of potent vasoconstrictors, and perturbations in the integrity of the neurovascular unit likely contribute to progressive neurodegenerative processes. The accumulation of misfolded proteins coincides with the anatomical distribution observed in the early stages of both Alzheimer's and Parkinson's diseases. We contend misfolding of hyperphosphorylated tau (HPπ), alpha-synuclein, and beta-amyloid could represent a compensatory early protective response to the sustained systemic and brain inflammation. However, we favor the view that the chronic systemic and brain dysregulated inflammation and the diffuse vascular damage contribute to the establishment of neurodegenerative processes with childhood clinical manifestations. Friend turns Foe early; therefore, implementation of neuroprotective measures to ameliorate or stop the inflammatory and neurodegenerative processes is warranted in exposed children. Epidemiological, cognitive, structural, and functional neuroimaging and mechanistic studies into the association between air pollution exposures and the development of neuroinflammation and neurodegeneration in children are of pressing importance for public health.

Mitoprotective effect of Centella asiatica against aluminum-induced neurotoxicity in rats: possible relevance to its anti-oxidant and anti-apoptosis mechanism

Role of mitochondrial dysfunction and oxidative stress has been well documented in various cognitive-related disorders such as Alzheimer's disease. Aluminum is a neurotoxic metal that may be involved in the progression of neurodegenerative processes. The antioxidant and memory enhancing effects of Centella asiatica (CA) are well known in the last few decades. Therefore, the present study has been designed to explore the neuroprotective effect of CA on chronic aluminum exposure induced mitochondrial enzyme alteration, oxidative stress, apoptosis and cognitive dysfunction in rat. Aluminum (100 mg/kg) and CA (150 and 300 mg/kg) were administered daily for a period of 6 weeks in male Wistar rats. Various behavioral, biochemical and cellular estimations and aluminum concentration were assessed. Chronic aluminum administration resulted in memory impairment and caused marked oxidative damage associated with mitochondria impairment. It also caused a significant increase in caspase-3 activity, acetylcholine esterase activity and aluminum concentration in hippocampus and cerebral cortex of rat brain. Chronic administration of CA significantly improved memory performance, oxidative defense decreased aluminum concentration, caspase-3, acetylcholinestrease activity and reversal of mitochondrial enzyme activity as compared to aluminum-treated animals. Results of the study demonstrate neuroprotective potential of CA against aluminum-induced cognitive dysfunction and mito- oxidative damage.

Secreted phospholipase A2 group IIA is a neurotoxin released by stimulated human glial cells

Neuroinflammation, which is one of the hallmarks of neurodegenerative disorders such as Alzheimer's disease, involves secretion of pro-inflammatory mediators by activated glial cells. Secreted phospholipase A2 group IIA (sPLA2IIA) has been implicated as an inflammatory mediator contributing to various peripheral inflammatory conditions; however, little is known about the role this enzyme plays in neuroinflammation. Human microglia-like promonocytic THP-1 cells and human primary astrocytes were used to study sPLA2IIA expression, secretion and function. Production of sPLA2IIA by these cells was induced in response to stimulation by pro-inflammatory mediators at both mRNA and protein levels. Removal of sPLA2IIA from stimulated human microglia-like cell and astrocyte supernatants by immunosorbent caused significant reduction of their toxicity towards SH-SY5Y neuroblastoma cells. Both sPLA2IIA specific and non-specific PLA2 inhibitors exhibited no anti-cytotoxic or neuroprotective effects, suggesting that sPLA2IIA cytotoxicity is mediated by a non-enzymatic mechanism. The data obtained indicate that sPLA2IIA may contribute to the pathogenesis of neurodegenerative diseases involving neuroinflammation. Agents inhibiting the non-enzymatic actions of sPLA2IIA could be used to slow down progression of neurodegenerative processes that are driven by inflammation.

Microglia-inhibiting activity of Parkinson's disease drug amantadine

Amantadine is currently used as an antiviral and an antiparkinsonian drug. Although the drug is known to bind a viral proton channel protein, the mechanism of action in Parkinson's disease (PD) remains to be determined. This study investigated whether the drug has an inhibitory effect on microglial activation and neuroinflammation, which have been implicated in the progression of neurodegenerative processes. Using cultured microglial cells, it was demonstrated that the drug inhibited inflammatory activation of microglia and a signaling pathway that governs the microglial activation. The drug reduced the expression and production of proinflammatory mediators in bacterial lipopolysaccharide-stimulated microglia cells. The microglia-inhibiting activity of amantadine was also demonstrated in a microglia/neuron coculture and animal models of neuroinflammation and Parkinson's disease. Collectively, our results suggest that amantadine may act on microglia in the central nervous system to inhibit their inflammatory activation, thereby attenuating neuroinflammation. These results provide a molecular basis of the glia-targeted mechanism of action for amantadine.

No influence of KIF1B on neurodegenerative markers in multiple sclerosis

In search of genetic causes of multiple sclerosis (MS), a number of genes have consistently shown association with MS susceptibility in the past couple of years.1 All of these identified genes are directly or indirectly involved with the inflammatory process. However, it has become increasingly clear that MS consists of both an inflammatory and a progressive neurodegenerative process,2 which is illustrated by the fact that new and potent anti-inflammatory drugs have been unable to halt neurodegeneration. The relation between episodes of inflammation and the neurodegenerative component characterized by irreversible axonal loss are far from clear at this point. Some authors have argued that neurodegeneration is independent of inflammation, while others argue that the 2 components are closely associated and are actually interdependent.2,3 The neurodegenerative component is clinically highly relevant since it is held predominantly responsible for disability accumulation, although several questions regarding this issue remain.2 Until recently, no genetic marker for neurodegeneration in MS was identified. However, in 2008, it was reported for the first time that a “neurodegenerative gene,” i.e., the KIF1B rs10492972 [C] variant, was associated with MS susceptibility.4 KIF1B is involved in axonal transport of mitochondria and synaptic vesicle precursors. Dysregulation of axonal transport plays a role in several neurodegenerative diseases.4 The authors suggested that KIF1B could be the first gene involved in MS susceptibility with a possible neurodegenerative effect.4 Unfortunately, this finding could later not be confirmed in other …

Neuroinflammation and α-Synuclein Dysfunction Potentiate Each Other, Driving Chronic Progression of Neurodegeneration in a Mouse Model of Parkinson’s Disease

BackgroundMechanisms whereby gene–environment interactions mediate chronic, progressive neurodegenerative processes in Parkinson’s disease (PD)—the second most common neurodegenerative disease—remain elusive.ObjectiveWe created a two-hit [neuroinflammation and mutant α-synuclein (α-syn) overexpression] animal model to investigate mechanisms through which mutant α-syn and inflammation work in concert to mediate chronic PD neurodegeneration.MethodsWe used an intraperitoneal injection of the inflammogen lipopolysaccharide (LPS; 3 × 106 EU/kg) to initiate systemic and brain inflammation in wild-type (WT) mice and transgenic (Tg) mice overexpressing human A53T mutant α-syn. We then evaluated nigral dopaminergic neurodegeneration, α-syn pathology, and neuroinflammation.ResultsAfter LPS injection, both WT and Tg mice initially displayed indistinguishable acute neuroinflammation; however, only Tg mice developed persistent neuroinflammation, chronic progressive degeneration of the nigrostriatal dopamine pathway, accumulation of aggregated, nitrated α-syn, and formation of Lewy body-like inclusions in nigral neurons. Further mechanistic studies indicated that 4-week infusion of two inhibitors of inducible nitric oxide synthase and NADPH oxidase, major free radical–generating enzymes in activated microglia, blocked nigral α-syn pathology and neurodegeneration in LPS-injected Tg mice.ConclusionsMicroglia-derived oxidative stress bridged neuroinflammation and α-syn pathogenic alteration in mediating chronic PD progression. Our two-hit animal model involving both a genetic lesion and an environmental trigger reproduced key features of PD and demonstrated synergistic effects of genetic predisposition and environmental exposures in the development of PD. The chronic progressive nature of dopaminergic neurodegeneration, which is absent in most existing PD models, makes this new model invaluable for the study of mechanisms of PD progression.

Pluripotent stem cells - A review of the current status in neural regeneration

Pharmacological or neurosurgical therapies currently in practice to treat the damage in various neurodegenerative disorders are not efficient in preventing progression or cure of these progressive neurodegenerative processes. Recently, a new approach, cell therapy using stem cell, is being evaluated. However, the use of this therapy in the treatment of these neurological diseases is highly restricted, mainly owing to several technical difficulties and limitations. The strategy of isolation and characterization of neural stem cells from various sources will probably provide a major impetus and open up an interesting, novel therapeutic modality for several neurodegenerative disorders. The high regenerative potential of damaged neural tissues suggests that various embryonic/adult sources serve as a proxy for neural stem cells for cell-based therapy.

The Contributions Of Antioxidant Activity Of Lipoic Acid In Reducing Neurogenerative Progression Of Parkinson’s Disease: A Review

ABSTRACTThis work reviews the evidence of the mechanism of neuronal degeneration in Parkinson's disease (PD) and the neuroprotective effect of lipoic acid and its use in the treatment of PD. PD is characterized by slow and progressive degeneration of dopaminergic neurons of the substantia nigra pars compacta, leading to reduction of the striatal dopaminergic terminals. It is known that several factors influence neuronal damage. Among these factors, oxidative stress, immune system activity, microglial cells, and apoptotic mechanisms are of major importance. Currently, several antioxidants have been studied with the aim of reducing/slowing the progression of neurodegenerative processes. Lipoic acid is considered a universal antioxidant because it is an amphipathic substance. Lipoic acid and its reduced form, dihidrolipoic acid, act against reactive oxygen species, reducing oxidative stress. Therefore, this antioxidant has been used in the treatment of many diseases, including a new perspective for the treatment of Parkinson's disease.

Mitochondrial dementia: A sporadic case of progressive cognitive and behavioral decline with hearing loss due to the rare m.3291T>C MELAS mutation

We report the case of a 23-year-old Italian female harboring the rare m.3291T>C mutation in the MT-TL1 gene, that encodes the mitochondrial transfer RNA for leucine 1 (UUA/G). MT-TL1 mutations usually cause the MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) syndrome. Our patient, however, suffered from a non-syndromic mitochondrial disorder (MID), clinically characterized by progressive cognitive and behavioral decline, and hearing loss; brain MRI disclosed diffuse supratentorial and infratentorial atrophy; EKG revealed a Wolff–Parkinson–White syndrome; combined neuroleptic and antidepressant treatment markedly improved her behavioral symptoms. This case expands the clinical spectrum of non-syndromic MIDs, and further confirms that no obvious genotype–phenotype correlation exists for the m.3291T>C DNA mutation; indeed, this mutation has been previously reported in a Japanese child, who suffered from MELAS, and in an Italian child, who presented an apparently isolated mild myopathy. Moreover, it supports the hypothesis that at least in MT-TL1-related MIDs, dementia may be caused by a progressive neurodegenerative process, rather than by injury accumulation due to stroke-like episodes. Finally, our case suggests that common neuroleptic and antidepressant drugs may be clinically efficacious in the management of psychiatric symptoms associated with MIDs.

Acute Progression of Neuromuscular Findings in Infantile Pompe Disease

A 2-year-old girl with Pompe disease developed an acute worsening of muscle weakness during a hospitalization, and required intubation for an upper respiratory infection. Electromyography and nerve conduction studies produced results consistent with a severe chronic motor axonal peripheral polyneuropathy, with no evidence of reinnervation. Magnetic resonance imaging of the brain demonstrated generalized hypomyelination and parenchymal volume loss, whereas magnetic resonance spectroscopy suggested neuronal injury and hypomyelination. This case provides compelling evidence for a slowly progressive neurodegenerative process in patients with infantile Pompe disease, affecting the motor neurons. Routine electromyography, nerve conduction studies, and cranial magnetic resonance imaging should be considered to delineate the presence of a neurodegenerative process in infantile-onset Pompe disease.

P3.064 Immunohistochemical study of the progression of neurodegenerative process within the striatum of rats transgenic for Huntington's disease

P3.064 Immunohistochemical study of the progression of neurodegenerative process within the striatum of rats transgenic for Huntington's disease