Journal of Parkinson’s Disease and Alzheimer’s Disease最新文献

{"title":"Amantadine Treatment for Parkinson’s Disease during COVID-19: Bimodal Action Targeting Viral Replication and the NMDA Receptor","authors":"","doi":"10.13188/2376-922x.1000030","DOIUrl":"https://doi.org/10.13188/2376-922x.1000030","url":null,"abstract":"Parkinson’s Disease [PD] and COVID-19 share common features that include age dependency and their association with co-morbidities such as cardiovascular disease, diabetes and respiratory problems. Shortness of breath [dyspnea] is a feature of both conditions. Symptoms of PD are known to deteriorate during systemic infections and common features of COVID-19 [fever, delirium, stress] may aggravate tremor, gait and dyskinesias in PD. Parkinsonism is a feature of many viral encephalatides with associated basal ganglia neuropathology. Following uptake from the circulation or via the upper nasal transcribial route, the spike protein of SARS-CoV-2 binds to a host cell protein ACE2 expressed on neurons and neuroglia. Essential host cell proteases such as Cathepsin L [CTSL] then cleave the spike protein leading to fusion of viral and host cell membranes and release of the viral genome into the host cell. Cryo-microscopic studies confirm that SARS-CoV-2 binds with high affinity to ACE2. High throughput drug screen gene expression analysis of 466 agents with the potential to down-regulate expression of CTSL identified amantadine which ranked 5th in efficacy. A link between viral infection and treatment of PD by amantadine started serendipitously with the report of a PD patient noting improvement of tremor and rigidity after treatment with amantadine for influenza A infection. Amantadine’s beneficial action in PD relates to its ability to indirectly replenish dopaminergic activity via stimulation of the NMDA subclass of ionotropic glutamate receptors. An NMDA receptor antagonist was effective in limiting viral replication with improvement of neurological symptoms due to infection with HCoV-OC43. The ability of amantadine to exert beneficial effects in COVID-19 is worthy of clinical investigation.","PeriodicalId":307684,"journal":{"name":"Journal of Parkinson’s Disease and Alzheimer’s Disease","volume":"20 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2020-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"114628619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Amantadine for the Treatment of Parkinson’s Disease and its Associated Dyskinesias","authors":"","doi":"10.13188/2376-922x.1000031","DOIUrl":"https://doi.org/10.13188/2376-922x.1000031","url":null,"abstract":"Disturbances of motor function characteristic of Parkinson’s Disease (PD) are commonly treated with L-Dopa. However, prolonged treatment commonly results in L-Dopa-Induced Dyskinesias (LIDs) with high negative impact on patient’s quality of life that seriously limits the use of L-Dopa. Amantadine, like L-Dopa, is effective for the replenishment of defective dopamine production in PD by mechanisms involving increased synthesis and decreased synaptic reuptake with consequent improvements of the patient’s motor symptoms. Results of RCTs and meta-analyses continue to support the claim that amantadine is effective for the treatment of early or stable PD. Preclinical and clinical studies reveal that LIDs result from modifications of corticostriatal (glutamatergic) and nigrostrial (dopaminergic) connectivity resulting from the relative over-activation of NMDA receptors, a phenomenon shown to occur in patients with LIDs using Positron Emission Tomography. In addition to its beneficial actions in restoring dopaminergic function, amantadine is a potent non-competitive NMDA receptor antagonist and, as such, affords a potentially effective agent for the treatment for LIDs. Indeed, beneficial effects of amantadine for the treatment of LIDs have been described in multiple Randomized Controlled Trials (RCTs) using a range of wellestablished dyskinesia rating scales over the last two decades and extended-release formulations of amantadine have also been found to be effective. Confirmation of clinical efficacy of amantadine for the treatment of LIDs has been complemented by the results of systematic reviews and meta-analyses that include a Movement Disease Society (MDS)-commissioned evidence-based update of treatment options. Treatment of PD patients with amantadine during the COVID-19 pandemic could be advantageous since, in addition to its ability to correct the movement disorder and dyskinesias, amantadine has the potential to limit replication of SARS-CoV-2, the virus responsible for COVID-19.","PeriodicalId":307684,"journal":{"name":"Journal of Parkinson’s Disease and Alzheimer’s Disease","volume":"33 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2020-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"124808155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alzheimer’s Disease: Adult-Onset of Inborn Error of Methionine Metabolism","authors":"A. Soloway","doi":"10.13188/2376-922x.1000026","DOIUrl":"https://doi.org/10.13188/2376-922x.1000026","url":null,"abstract":"The cause and treatment of Alzheimer’s Disease remains obscure. It could arise from adult onset of an inborn error of metabolism of the essential amino acid methionine expressed through an alternate biochemical pathway for methionine metabolism. This latter pathway generates homocysteine directly from methionine, accounting for the latter’s elevated vascular concentration in Alzheimer’s patients and those predisposed to this disease. Through this alternate pathway, synthesis of S-adenosylmethionine, an important component in memory retention, is precluded and accounts for the symptoms observed in patients. Suggestions for methods to increase brain concentrations of S-adenosylmethionine are presented. Alzheimer’s disease (AD) and related dementias currently affect approximately 5.4 million Americans (one out of eight older adults), and similar results are observed in other developed countries. It is the sixth leading cause of death in the U.S. and the only one in the top ten whose origin and effective treatment remain unknown [1]. The biggest risk factor for developing AD is age, and approximately one-third of those over 85 have some form of dementia. Since women live longer than men, they are at greater risk for developing AD. The financial costs in the U.S. of caring for individuals afflicted with AD and related dementia have been estimated to be $226 billion in 2015; and, without major improvement in early diagnosis and effective treatment, these costs are projected to rise to $1 trillion by 2050 [2]. Therefore, understanding the cause of AD has become a major health imperative. In an earlier publication, we proposed the possibility that AD might be related to an unexpected pathway in methionine metabolism [3]. The basis for such speculation stemmed from the observation that higher concentrations of homocysteine have been observed in the blood of patients with AD and those at risk for developing AD [4-8]. The source for such elevated homocysteine levels still remains obscure, but it could arise from the direct metabolism of methionine to homocysteine. It is also noteworthy that blood and brain concentrations of S-adenosylmethionine (SAM), an important biochemical for normal homeostasis, are severely depressed in AD patients [9]. The basis for this occurrence could be the unavailability of methionine to form SAM. From animal models, it has been determined that SAM is of critical importance in maintaining cognitive functions, especially memory retention [10]. All of these observations are consistent with and support the hypothesis of the operation of an alternate pathway in methionine metabolism. The basis for AD may be an adult-onset of an Inborn Error of Metabolism (IEM) of methionine. The term IEM was first proposed by Archibald Garrod and related to adult diseases [11]. However, the Figure 1: Diagram showing the pathway for the metabolism of methionine. This process enables maintenence of normal levels of SAM [22]. Citation: Soloway AH. Alzhe","PeriodicalId":307684,"journal":{"name":"Journal of Parkinson’s Disease and Alzheimer’s Disease","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"121047018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Magnesium Serum Concentrations in Patients with Dementia Vs. Controls; A Systematic Review and Meta-Analysis","authors":"G. Koren","doi":"10.13188/2376-922x.1000032","DOIUrl":"https://doi.org/10.13188/2376-922x.1000032","url":null,"abstract":"Background: The role of magnesium in the pathogenesis of dementia and other degenerative disorders has focused attention in recent years. There have been several studies reporting favorable effects of magnesium in the treatment of various degenerative illnesses. In contrast, other research found that both low and high serum magnesium levels were associated with an increased risk of Alzheimer’s disease and mixed dementia. These contrasting results render the role of magnesium levels in dementia unclear. Our objective was to investigate the possible association between dementia and hypomagnesaemia. Methods: We conducted a systematic review and meta-analysis of all articles, in any language, reporting on serum magnesium concentrations either in plasma or serum of patients with dementia, compared to patients without dementia. Studies reporting on proportion of hypomagnesaemia patients and not mean levels were excluded. Results: Seven studies were accepted for the meta-analysis, reporting on 2932 dementia cases and 42920 controls. All types of dementia were reported. There was a significant heterogeneity in the results, and the difference in Mg2+ concentrations between patients with dementia and controls was not significant (mean difference -10.68 micromole/L (95% confidence interval -30.62 and +9.27). There were no significant differences in the measured levels of the different types of dementia. Conclusions: Our study, based on large numbers of dementia patients and controls, suggests that low serum magnesium concentrations are not associated with increased risk of dementia. This may be explained by poor correlation between serum and tissue distribution of magnesium and by the fact that less than one percent of total body magnesium circulates in the blood. [3]. Low magnesium levels were found to be decreased in various tissues of patients with Alzheimer’s disease in clinical, experimental, and autopsy studies [4]. A reduction in the frequency of intracellular magnesium deposits in neurons of Alzheimer’s patients was reported. Decrease in magnesium and glutamic acid have been shown in the hippocampal tissue of Alzheimer’s disease patients [5]. There is evidence that glutamate release and intake are chronically disturbed in Alzheimer’s disease, and glutamate levels are possibly increased in the synaptic cleft, with resultant calcium influx to postsynaptic neurons and activation of the calcium related enzyme system. This leads to production of free radicals, protein destruction, lipid peroxidation, and neuron death with DNA destruction [4]. Increasing volume of research has explored the connection between magnesium and the role of NMDA receptors in degenerative brain disorders. NMDA receptors have a critical role the central nervous system, including neuronal development, plasticity and neurodegeneration [1, 3]. These receptors lead to channels which are permeable to calcium, sodium and potassium ions and voltagegated channels blocked by magnesium ions","PeriodicalId":307684,"journal":{"name":"Journal of Parkinson’s Disease and Alzheimer’s Disease","volume":"102 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"1900-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"131683368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autophagy Monitoring in Cerebral Pericytes from Alzheimer’s disease Mouse Model in an Inflammatory Environment","authors":"P. Guylène","doi":"10.13188/2376-922x.1000033","DOIUrl":"https://doi.org/10.13188/2376-922x.1000033","url":null,"abstract":"Background: The blood-brain barrier (BBB) is a complex neurovascular unit involving pericytes as multi-functional cells that play a crucial role in maintaining homeostasis. In Alzheimer’s disease (AD), platelet-derived growth factor receptor-β (PDGFR β ) immunostaining revealed significantly reduced pericyte coverage of brain capillaries as well as reduced pericyte numbers in AD cortex and hippocampus compared with control brains. However, the mechanisms of pericyte loss have yet to be completely defined. Moreover, we have previously shown that, in microglia, interleukin-1 β (IL-1 β )-induced inflammation blocks autophagic flow, a physiological process involved in the degradation of proteins including the β -amyloid peptide. Thus, we evaluated whether the inflammatory response in AD impaired autophagy in pericytes. Methods: A longitudinal autophagic status monitoring was performed in pericytes purified from brains of AD and wild type (WT) mice at 3, 6 and 12 months. Furthermore, the impact of an inflammatory environment was studied not only in these primary pericytes but also in a pericyte cell line developed in the laboratory. Results: Primary pericytes from AD mice displayed a significant increase of autophagic markers at 3 months whereas in later stages their expressions were like those of WT mice. In addition, IL-1 β -induced inflammation did not modify the expression of autophagic markers and not those of mTOR signaling pathway in both primary and immortalized mouse pericytes. Conclusions: For the first time, these data highlighted that autophagy is activated in primary pericytes from AD transgenic mice at 3 months. In addition, inflammation has no impact on autophagic flow under our experimental conditions.","PeriodicalId":307684,"journal":{"name":"Journal of Parkinson’s Disease and Alzheimer’s Disease","volume":"15 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"1900-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"123664121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}