Pub Date : 2017-11-24DOI: 10.4172/2161-0460.1000402
K. Hori, Kimiko Konishi, Misa Hosoi, Michiho Sodenaga, Hiroyuki Kamatani, H. Tomioka, M. Hachisu
We encountered a 79 year old female patient with mild cognitive impairment who showed sustained improvement to an almost normal level of global cognitive function for >1 year when treated with donepezil. Her levels of high-sensitivity C-reactive protein (hs-CRP) also showed a sustained decrease with treatment. Here, we describe the clinical changes in her cognition and discuss the relationship between cognitive function and low-grade inflammation, focusing on three important issues. First, cognitive dysfunction may be related to low-grade inflammation. Second, hs-CRP may be a suitable marker for this low-grade inflammation. Third, treatment with cholinesterase inhibitors was effective, either by suppressing this low-grade inflammation or by upregulating acetylcholine, which suppresses such inflammation. In this patient, inflammation appeared to be related to the cholinergic anti-inflammatory pathway.
{"title":"Case Report: High-Sensitivity C-Reactive Protein is a Potentially Useful Marker of the Need for Psychotic Treatment for Cognitive Dysfunction Related to Low-Grade Inflammation","authors":"K. Hori, Kimiko Konishi, Misa Hosoi, Michiho Sodenaga, Hiroyuki Kamatani, H. Tomioka, M. Hachisu","doi":"10.4172/2161-0460.1000402","DOIUrl":"https://doi.org/10.4172/2161-0460.1000402","url":null,"abstract":"We encountered a 79 year old female patient with mild cognitive impairment who showed sustained improvement to an almost normal level of global cognitive function for >1 year when treated with donepezil. Her levels of high-sensitivity C-reactive protein (hs-CRP) also showed a sustained decrease with treatment. Here, we describe the clinical changes in her cognition and discuss the relationship between cognitive function and low-grade inflammation, focusing on three important issues. First, cognitive dysfunction may be related to low-grade inflammation. Second, hs-CRP may be a suitable marker for this low-grade inflammation. Third, treatment with cholinesterase inhibitors was effective, either by suppressing this low-grade inflammation or by upregulating acetylcholine, which suppresses such inflammation. In this patient, inflammation appeared to be related to the cholinergic anti-inflammatory pathway.","PeriodicalId":15012,"journal":{"name":"Journal of Alzheimers Disease & Parkinsonism","volume":"33 1","pages":"1-3"},"PeriodicalIF":0.0,"publicationDate":"2017-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76715876","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}
Pub Date : 2017-11-23DOI: 10.4172/2161-0460.1000400
T. Smolek, S. Jadhav, B. Valachova, Thomas Vogels, J. Legáth, P. Novak, N. Zilka
Tauopathies represent a group of neurodegenerative disorders characterised by the accumulation of conformationally altered tau protein. Alzheimer’s disease (AD) is the most prevalent primary tauopathy. In AD, tau pathology progressively spreads across a stereotypical sequence of anatomically connected brain regions. In early stages, the disease manifests in the locus coeruleus and entorhinal cortex; at later stages it spreads through the hippocampus to cortical brain areas. Recent studies suggest that spreading of pathological tau occurs predominantly through neuron-to-neuron transmission; however, glial cells can also be involved in this process. Propagation depends on the conformational state and post-translational modifications of tau protein of various tau strains. Abnormal tau can subsequently act as a seed, misfolding and aggregating normal tau proteins inside the cells. Several research groups have successfully recapitulated tau transmission in animal models. Currently, we are able to induce and drive tau neurodegeneration by using tau species isolated from diseased human brains. Such state-of-the-art “humanised” animal models represent a powerful tool for development of new drug leads and diagnostics for human tauopathies.
{"title":"Transmission of Tau Pathology from Human to Rodent Brain: How to Humanise Animal Models for Alzheimer’s Disease Research","authors":"T. Smolek, S. Jadhav, B. Valachova, Thomas Vogels, J. Legáth, P. Novak, N. Zilka","doi":"10.4172/2161-0460.1000400","DOIUrl":"https://doi.org/10.4172/2161-0460.1000400","url":null,"abstract":"Tauopathies represent a group of neurodegenerative disorders characterised by the accumulation of conformationally altered tau protein. Alzheimer’s disease (AD) is the most prevalent primary tauopathy. In AD, tau pathology progressively spreads across a stereotypical sequence of anatomically connected brain regions. In early stages, the disease manifests in the locus coeruleus and entorhinal cortex; at later stages it spreads through the hippocampus to cortical brain areas. Recent studies suggest that spreading of pathological tau occurs predominantly through neuron-to-neuron transmission; however, glial cells can also be involved in this process. Propagation depends on the conformational state and post-translational modifications of tau protein of various tau strains. Abnormal tau can subsequently act as a seed, misfolding and aggregating normal tau proteins inside the cells. Several research groups have successfully recapitulated tau transmission in animal models. Currently, we are able to induce and drive tau neurodegeneration by using tau species isolated from diseased human brains. Such state-of-the-art “humanised” animal models represent a powerful tool for development of new drug leads and diagnostics for human tauopathies.","PeriodicalId":15012,"journal":{"name":"Journal of Alzheimers Disease & Parkinsonism","volume":"1 1","pages":"1-10"},"PeriodicalIF":0.0,"publicationDate":"2017-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88602533","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}
Pub Date : 2017-11-23DOI: 10.4172/2161-0460.1000401
Takayuki Kikukawa, H. Saito, Itsuki Hasegawa, J. Takeuchi, Akitoshi Takeda, J. Kawabe, Yasuhiro Wada, A. Mawatari, Yasuyoshi Watanabe, S. Kitamura, H. Shimada, M. Higuchi, T. Suhara, Y. Itoh
Objective: Different regional specificity in tau accumulation is well known in Alzheimer’s disease (AD) brains. However, little is known about such distribution in aging brains and mild cognitive impairment (MCI) brains. Methods: Cognitive functions and regional accumulation of tau and amyloid β (Aβ) were evaluated in 13 healthy controls (HCs), 3 patients with MCI and 4 AD patients. Tau and Aβ accumulation was semi-quantitatively measured with positron emission tomography (PET) using [11C]pyridinyl-butadienyl-benzothiazole 3 (PBB3) and [11C]Pittsburgh compound-B (PiB). Results: Age-dependent accumulation of tau was found in all predetermined regions characteristic of AD, especially in the parahippocampal gyrus, lateral temporal cortex, frontal cortex, and posterior cingulate gyrus, where age-dependency was statistically significant. In contrast, age-dependency in accumulation of Aβ was not observed in most regions assessed in HC. Moreover, the accumulation of tau in regions characteristic of AD in MCI patients was higher than that in HC, whereas tau accumulation was highest and statistically significant in AD patients. Unlike HC, the accumulation of tau was accompanied by that of Aβ in patients with MCI and AD. Conclusion: Mild and age-dependent accumulation of tau without Aβ was found in AD-related areas in aging brains. Considering age as a major risk for AD, higher accumulation of tau may trigger the neurodegenerative process of AD.
{"title":"Localized Accumulation of Tau without Amyloid-Beta in Aged Brains Measured with [11C]PBB3 and [11C]Pib Positron Emission Tomography","authors":"Takayuki Kikukawa, H. Saito, Itsuki Hasegawa, J. Takeuchi, Akitoshi Takeda, J. Kawabe, Yasuhiro Wada, A. Mawatari, Yasuyoshi Watanabe, S. Kitamura, H. Shimada, M. Higuchi, T. Suhara, Y. Itoh","doi":"10.4172/2161-0460.1000401","DOIUrl":"https://doi.org/10.4172/2161-0460.1000401","url":null,"abstract":"Objective: Different regional specificity in tau accumulation is well known in Alzheimer’s disease (AD) brains. However, little is known about such distribution in aging brains and mild cognitive impairment (MCI) brains. Methods: Cognitive functions and regional accumulation of tau and amyloid β (Aβ) were evaluated in 13 healthy controls (HCs), 3 patients with MCI and 4 AD patients. Tau and Aβ accumulation was semi-quantitatively measured with positron emission tomography (PET) using [11C]pyridinyl-butadienyl-benzothiazole 3 (PBB3) and [11C]Pittsburgh compound-B (PiB). Results: Age-dependent accumulation of tau was found in all predetermined regions characteristic of AD, especially in the parahippocampal gyrus, lateral temporal cortex, frontal cortex, and posterior cingulate gyrus, where age-dependency was statistically significant. In contrast, age-dependency in accumulation of Aβ was not observed in most regions assessed in HC. Moreover, the accumulation of tau in regions characteristic of AD in MCI patients was higher than that in HC, whereas tau accumulation was highest and statistically significant in AD patients. Unlike HC, the accumulation of tau was accompanied by that of Aβ in patients with MCI and AD. Conclusion: Mild and age-dependent accumulation of tau without Aβ was found in AD-related areas in aging brains. Considering age as a major risk for AD, higher accumulation of tau may trigger the neurodegenerative process of AD.","PeriodicalId":15012,"journal":{"name":"Journal of Alzheimers Disease & Parkinsonism","volume":"61 1","pages":"1-7"},"PeriodicalIF":0.0,"publicationDate":"2017-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86366013","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}
Pub Date : 2017-11-16DOI: 10.4172/2161-0460.1000399
Yuhai Zhao, L. Cong, V. Jaber, W. Lukiw
Our ongoing appreciation of the magnitude and complexity of the human microbiome has resulted in a reassessment of many fundamental concepts of the contribution of the microbial community to neurological health and disease. The assumption of the privileged immunological and compartmentalized status of the human central nervous system (CNS) has been recently challenged in multiple investigations - particularly because microbial-derived nucleic acid sequences and highly neurotoxic and pro-inflammatory exudates representative of gastrointestinal (GI) tract Gram-negative anaerobic bacteria are showing up within CNS compartments. Unanticipated microbial presence has also recently been discovered in the anatomical regions of the CNS implicated in pro-inflammatory pathological signaling and neuro-immune disruptions that characterize progressive and lethal neurodegenerative diseases of the CNS such as Alzheimer’s disease (AD). This communication (i) will briefly review some very recent research on the contribution of the GI tract microbiome and microbial neurotoxins to inflammatory neurodegeneration in the CNS with emphasis on AD wherever possible; (ii) will review the evidence that the GI tract microbiome may have an increasing inter-relationship with the CNS via leaky barriers as we age; and (iii) will review recent experimental findings that support the intriguing possibility that the CNS may possess its own microbiome whose basal complexity is in part derived from the GI tract microbiome of the host
{"title":"Gastrointestinal (GI) Tract Microbes and Microbial Neurotoxins in the Human Central Nervous System (CNS) in Alzheimer’s Disease (AD)","authors":"Yuhai Zhao, L. Cong, V. Jaber, W. Lukiw","doi":"10.4172/2161-0460.1000399","DOIUrl":"https://doi.org/10.4172/2161-0460.1000399","url":null,"abstract":"Our ongoing appreciation of the magnitude and complexity of the human microbiome has resulted in a reassessment of many fundamental concepts of the contribution of the microbial community to neurological health and disease. The assumption of the privileged immunological and compartmentalized status of the human central nervous system (CNS) has been recently challenged in multiple investigations - particularly because microbial-derived nucleic acid sequences and highly neurotoxic and pro-inflammatory exudates representative of gastrointestinal (GI) tract Gram-negative anaerobic bacteria are showing up within CNS compartments. Unanticipated microbial presence has also recently been discovered in the anatomical regions of the CNS implicated in pro-inflammatory pathological signaling and neuro-immune disruptions that characterize progressive and lethal neurodegenerative diseases of the CNS such as Alzheimer’s disease (AD). This communication (i) will briefly review some very recent research on the contribution of the GI tract microbiome and microbial neurotoxins to inflammatory neurodegeneration in the CNS with emphasis on AD wherever possible; (ii) will review the evidence that the GI tract microbiome may have an increasing inter-relationship with the CNS via leaky barriers as we age; and (iii) will review recent experimental findings that support the intriguing possibility that the CNS may possess its own microbiome whose basal complexity is in part derived from the GI tract microbiome of the host","PeriodicalId":15012,"journal":{"name":"Journal of Alzheimers Disease & Parkinsonism","volume":"29 1","pages":"1-6"},"PeriodicalIF":0.0,"publicationDate":"2017-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80972324","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}
Pub Date : 2017-11-09DOI: 10.4172/2161-0460.1000397
Tarun D. Singh, K. Josephs
Background: The annual number of neurodegenerative diseases among minorities is projected to increase by 524% between 1990 and 2040 in the US and there have been no studies looking at the incidence and prevalence of signs/symptoms among different racial and ethnic minority patients with Alzheimer's dementia (AD), Parkinson's disease (PD) and Motor neuron disease (MND).Methods: Retrospective review of all minority subgroups who presented to Mayo Clinic, Rochester (MN), with a diagnosis of AD, PD or MND between January 1st, 2000 and December 31st, 2015. We divided our study population into seven groups: Black, Asian, South Asian, Middle Eastern, Hispanic/Latino, American Indian/Alaskan Native and Native Hawaiian/Pacific Islander.Results: From a total of 8927 patients diagnosed with a neurodegenerative disease at our institution over the 15 year time frame, 472 were minority [PD=220 (46.6%); AD=90 (19.1%) and MND=162 (34.3%)]. The most common races/ethnicity were Black or African American in 135 (28.6%), Asian in 101 (21.4%), South Asian in 69 (14.6%), Middle eastern in 60 (12.7%), Hispanic/Latino in 59 (12.5%) and American Indian/Alaskan Native/Native Hawaiian/ Pacific Islander in 48 (10.2%). For PD, there were differences in the frequency of micrographia, anosmia, levodopa induced dyskinesia, falls and dystonia, while for AD there were differences in executive dysfunction and visual spatial changes and for MND difference were present for muscle atrophy, limb fasciculation, inability to ambulate, tongue fasciculation, choking episodes and dysphagia.Conclusion: Neurodegenerative diseases afflict all minority races and ethnicities, including some not previously reported and the frequency of presenting signs and symptoms significantly vary across different minority/ethnic groups.
{"title":"Symptom Prevalence of Neurodegenerative Diseases among Minorities","authors":"Tarun D. Singh, K. Josephs","doi":"10.4172/2161-0460.1000397","DOIUrl":"https://doi.org/10.4172/2161-0460.1000397","url":null,"abstract":"Background: The annual number of neurodegenerative diseases among minorities is projected to increase by 524% between 1990 and 2040 in the US and there have been no studies looking at the incidence and prevalence of signs/symptoms among different racial and ethnic minority patients with Alzheimer's dementia (AD), Parkinson's disease (PD) and Motor neuron disease (MND).Methods: Retrospective review of all minority subgroups who presented to Mayo Clinic, Rochester (MN), with a diagnosis of AD, PD or MND between January 1st, 2000 and December 31st, 2015. We divided our study population into seven groups: Black, Asian, South Asian, Middle Eastern, Hispanic/Latino, American Indian/Alaskan Native and Native Hawaiian/Pacific Islander.Results: From a total of 8927 patients diagnosed with a neurodegenerative disease at our institution over the 15 year time frame, 472 were minority [PD=220 (46.6%); AD=90 (19.1%) and MND=162 (34.3%)]. The most common races/ethnicity were Black or African American in 135 (28.6%), Asian in 101 (21.4%), South Asian in 69 (14.6%), Middle eastern in 60 (12.7%), Hispanic/Latino in 59 (12.5%) and American Indian/Alaskan Native/Native Hawaiian/ Pacific Islander in 48 (10.2%). For PD, there were differences in the frequency of micrographia, anosmia, levodopa induced dyskinesia, falls and dystonia, while for AD there were differences in executive dysfunction and visual spatial changes and for MND difference were present for muscle atrophy, limb fasciculation, inability to ambulate, tongue fasciculation, choking episodes and dysphagia.Conclusion: Neurodegenerative diseases afflict all minority races and ethnicities, including some not previously reported and the frequency of presenting signs and symptoms significantly vary across different minority/ethnic groups.","PeriodicalId":15012,"journal":{"name":"Journal of Alzheimers Disease & Parkinsonism","volume":"3 1","pages":"1-6"},"PeriodicalIF":0.0,"publicationDate":"2017-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80990877","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}
Pub Date : 2017-11-08DOI: 10.4172/2161-0460.1000396
R. Mauro, G. D. Lazzaro, T. Schirinzi, F. Martino, N. Mercuri, E. Fuccillo, A. Pisani, S. Girolamo
Background and objective: Non-motor symptoms (NMS) of Parkinson's disease (PD) are still underestimated and causative of disability and poor quality of life. Recently, it has been suggested that hearing impairment could be included into the spectrum of NMS, although both mechanisms and phenomenology are unclear. In this study we investigated the peripheral auditory pathway of PD, in patients with asymmetric rest tremor (ART) without dopaminergic denervation, and comparison with healthy controls (HC), aiming to detect differential alterations of cochlear functioning and medial olivocochlear system (MOC).Methods: 23 PD patients, 9 with ART and 19 HC were assessed for auditory functions with clinical examination and Transient-evoked otoacoustic emissions (TEOAEs). PD and ART groups were also evaluated with Unified Parkinson's Disease Rating Scale (UPDRS) II-III and Hoehn and Yahr scale. One-way ANOVA analysis and Pearson's test were performed to measure differences between groups and correlations.Results: TEOAE responses in PD patients were significantly lower compared to HC at 3 and 4 kHz, bilaterally. PD patients showed statistically significant lower TEOAEs at the same frequencies compared to ARTs. In addition, a MOC dysfunction in PD patients was observed. Conversely, no difference was found between ART and HC in all tests performed.Conclusion: PD patients, differently from both ART patients and HC, show abnormalities of basal TEOAEs at the highest frequencies. Auditory dysfunction correlates to motor disturbances, suggesting an underlying dopaminergic pathogenic mechanism. Early recognition of hearing impairment may represent a tool for patient assessment and help in the differential diagnosis in ART patients.
背景与目的:帕金森病(PD)的非运动症状(NMS)仍被低估，是导致残疾和生活质量下降的原因。近年来，有人提出听力障碍也可纳入NMS的范围，但其机制和现象学尚不清楚。在这项研究中，我们研究了PD患者的外周听觉通路，在不伴有多巴胺能去神经支配的非对称静止震颤(ART)患者中，并与健康对照(HC)进行比较，旨在检测耳蜗功能和内侧耳蜗系统(MOC)的差异改变。方法:采用临床检查和瞬时诱发耳声发射(teoae)对23例PD患者、9例ART患者和19例HC患者的听觉功能进行评估。采用统一帕金森病评定量表(UPDRS) II-III和Hoehn and Yahr量表对PD组和ART组进行评估。采用单因素方差分析和Pearson检验来衡量组间差异和相关性。结果:PD患者的TEOAE反应在双侧3和4 kHz时明显低于HC。PD患者在相同频率下的teoae比art患者低，具有统计学意义。此外，还观察到PD患者MOC功能障碍。相反，在进行的所有测试中，ART和HC之间没有发现差异。结论:PD患者基底teoae异常频率最高，与ART患者和HC患者不同。听觉功能障碍与运动障碍相关，提示潜在的多巴胺能致病机制。早期识别听力损伤可能是一种评估患者的工具，有助于ART患者的鉴别诊断。
{"title":"Assessment of Hearing Impairment in Parkinson's Disease: Implications for Differential Diagnosis and Disease Progression","authors":"R. Mauro, G. D. Lazzaro, T. Schirinzi, F. Martino, N. Mercuri, E. Fuccillo, A. Pisani, S. Girolamo","doi":"10.4172/2161-0460.1000396","DOIUrl":"https://doi.org/10.4172/2161-0460.1000396","url":null,"abstract":"Background and objective: Non-motor symptoms (NMS) of Parkinson's disease (PD) are still underestimated and causative of disability and poor quality of life. Recently, it has been suggested that hearing impairment could be included into the spectrum of NMS, although both mechanisms and phenomenology are unclear. In this study we investigated the peripheral auditory pathway of PD, in patients with asymmetric rest tremor (ART) without dopaminergic denervation, and comparison with healthy controls (HC), aiming to detect differential alterations of cochlear functioning and medial olivocochlear system (MOC).Methods: 23 PD patients, 9 with ART and 19 HC were assessed for auditory functions with clinical examination and Transient-evoked otoacoustic emissions (TEOAEs). PD and ART groups were also evaluated with Unified Parkinson's Disease Rating Scale (UPDRS) II-III and Hoehn and Yahr scale. One-way ANOVA analysis and Pearson's test were performed to measure differences between groups and correlations.Results: TEOAE responses in PD patients were significantly lower compared to HC at 3 and 4 kHz, bilaterally. PD patients showed statistically significant lower TEOAEs at the same frequencies compared to ARTs. In addition, a MOC dysfunction in PD patients was observed. Conversely, no difference was found between ART and HC in all tests performed.Conclusion: PD patients, differently from both ART patients and HC, show abnormalities of basal TEOAEs at the highest frequencies. Auditory dysfunction correlates to motor disturbances, suggesting an underlying dopaminergic pathogenic mechanism. Early recognition of hearing impairment may represent a tool for patient assessment and help in the differential diagnosis in ART patients.","PeriodicalId":15012,"journal":{"name":"Journal of Alzheimers Disease & Parkinsonism","volume":"42 1","pages":"1-4"},"PeriodicalIF":0.0,"publicationDate":"2017-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81543680","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}
Pub Date : 2017-11-03DOI: 10.4172/2161-0460.1000310
S. Fujiwara
α-synuclein (αSyn) is a 140 amino acid protein of unknown function, abundant in presynaptic terminals of nerve cells. Filamentous aggregates (amyloid fibrils) of αSyn have been shown to be involved with the pathogenesis of Parkinson’s disease, a progressive neurodegenerative disorder. Elucidation of the mechanism of amyloid fibril formation of αSyn is thus important for elucidation of the pathogenesis mechanism of this disease. Amyloid fibril formation is observed for many proteins including, for example, the amyloid-β peptide, the prion protein, and transthyretin. Extensive studies on amyloid fibril formation have characterized structural and kinetic properties of these proteins during fibril formation. Whereas involvement of unfolding/misfolding of the proteins with fibril formation implies that the dynamics of the proteins plays an important role in fibril formation, the dynamic aspects of fibril formation have not been explored very much. In this review, dynamic behavior of αSyn in the monomeric and fibril states is described, based on our recent study on the dynamics of αSyn using quasielastic neutron scattering, by which the dynamics of proteins can be directly measured. It was found that diffusive global motions of the entire molecules and segmental motions within the molecules are observed in the monomeric state but largely suppressed in the fibril state. On the other hand, the amplitudes of the local motions such as side chain motions were found to be larger in the fibril state than in the monomeric state. This implies that significant solvent space exists within the fibrils, which is attributed to αSyn molecule within the fibrils having a distribution of conformations. The larger amplitudes of the side chain motions in the fibril state than in the monomeric state imply that the fibril state is entropically favorable. Implications of this unusual dynamic behavior of αSyn fibrils are discussed in terms of possible clinical relevance.
{"title":"Dynamic Aspects of Amyloid Fibrils of ñ-Synuclein Related to thePathogenesis of ParkinsonâÂÂs Disease","authors":"S. Fujiwara","doi":"10.4172/2161-0460.1000310","DOIUrl":"https://doi.org/10.4172/2161-0460.1000310","url":null,"abstract":"α-synuclein (αSyn) is a 140 amino acid protein of unknown function, abundant in presynaptic terminals of nerve cells. Filamentous aggregates (amyloid fibrils) of αSyn have been shown to be involved with the pathogenesis of Parkinson’s disease, a progressive neurodegenerative disorder. Elucidation of the mechanism of amyloid fibril formation of αSyn is thus important for elucidation of the pathogenesis mechanism of this disease. Amyloid fibril formation is observed for many proteins including, for example, the amyloid-β peptide, the prion protein, and transthyretin. Extensive studies on amyloid fibril formation have characterized structural and kinetic properties of these proteins during fibril formation. Whereas involvement of unfolding/misfolding of the proteins with fibril formation implies that the dynamics of the proteins plays an important role in fibril formation, the dynamic aspects of fibril formation have not been explored very much. In this review, dynamic behavior of αSyn in the monomeric and fibril states is described, based on our recent study on the dynamics of αSyn using quasielastic neutron scattering, by which the dynamics of proteins can be directly measured. It was found that diffusive global motions of the entire molecules and segmental motions within the molecules are observed in the monomeric state but largely suppressed in the fibril state. On the other hand, the amplitudes of the local motions such as side chain motions were found to be larger in the fibril state than in the monomeric state. This implies that significant solvent space exists within the fibrils, which is attributed to αSyn molecule within the fibrils having a distribution of conformations. The larger amplitudes of the side chain motions in the fibril state than in the monomeric state imply that the fibril state is entropically favorable. Implications of this unusual dynamic behavior of αSyn fibrils are discussed in terms of possible clinical relevance.","PeriodicalId":15012,"journal":{"name":"Journal of Alzheimers Disease & Parkinsonism","volume":"32 1","pages":"1-4"},"PeriodicalIF":0.0,"publicationDate":"2017-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88404048","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}
Pub Date : 2017-10-30DOI: 10.4172/2161-0460.1000394
T. N. Goleva, A. Rogov, R. Zvyagilskaya
Alzheimer’s disease is a multifaceted, incurable neurologic disorder characterized by cognitive decline and degeneration of brain neurons. The main factors implicated in Alzheimer’s disease including accumulation of misfolded and aggregated proteins (hyperphosphorylated microtubule associated protein referred to as tau and amyloid Aβ), oxidative damage, inflammation, mitochondrial impairments and chronic energy imbalance, chronic endoplasmic reticulum stress, autophagy dysfunction, the abnormality and dysfunction of the mitochondrion-associated endoplasmic reticulum membrane serving as bridges between endoplasmic reticulum and mitochondria and regulating multiple functions such as Ca2+ transfer, energy exchange, lipid synthesis and transports and protein folding, genetic variation in lysosomal genes, metabolomic changes are shortly considered. A special emphasis was placed on mitochondrial fission (fragmentation) is a prominent early event preceding Alzheimer’s disease pathology in transgenic Aβ-animal models, as well as on marked decrease in extracellular amyloid deposition, prevention of the cognitive deficit development and improvement of synaptic parameters after inhibiting abnormalities in mitochondrial dynamics. The important role of the well-characterized Saccharomyces cerevisiae yeast as a valuable eukaryotic model organism in unraveling complex fundamental intracellular mechanisms underlying Alzheimer’s disease is highlighted. The benefits of applying a new model organism the yeast Yarrowia lipolytica, an obligate aerobe with the respiratory metabolism closely resembling that of mammalian cells, amenable to both classical and molecular genetic techniques, having a long history of use as a producer of heterological proteins, possessing an ability to change its morphology (from yeast-like to true mycelium) in response to environmental conditions as an useful alternative in deciphering a role of mitochondrial dynamics and distribution in an yeast model of Alzheimer’s disease are suggested.
{"title":"Alzheimer’s Disease: Molecular Hallmarks and Yeast Models","authors":"T. N. Goleva, A. Rogov, R. Zvyagilskaya","doi":"10.4172/2161-0460.1000394","DOIUrl":"https://doi.org/10.4172/2161-0460.1000394","url":null,"abstract":"Alzheimer’s disease is a multifaceted, incurable neurologic disorder characterized by cognitive decline and degeneration of brain neurons. The main factors implicated in Alzheimer’s disease including accumulation of misfolded and aggregated proteins (hyperphosphorylated microtubule associated protein referred to as tau and amyloid Aβ), oxidative damage, inflammation, mitochondrial impairments and chronic energy imbalance, chronic endoplasmic reticulum stress, autophagy dysfunction, the abnormality and dysfunction of the mitochondrion-associated endoplasmic reticulum membrane serving as bridges between endoplasmic reticulum and mitochondria and regulating multiple functions such as Ca2+ transfer, energy exchange, lipid synthesis and transports and protein folding, genetic variation in lysosomal genes, metabolomic changes are shortly considered. A special emphasis was placed on mitochondrial fission (fragmentation) is a prominent early event preceding Alzheimer’s disease pathology in transgenic Aβ-animal models, as well as on marked decrease in extracellular amyloid deposition, prevention of the cognitive deficit development and improvement of synaptic parameters after inhibiting abnormalities in mitochondrial dynamics. The important role of the well-characterized Saccharomyces cerevisiae yeast as a valuable eukaryotic model organism in unraveling complex fundamental intracellular mechanisms underlying Alzheimer’s disease is highlighted. The benefits of applying a new model organism the yeast Yarrowia lipolytica, an obligate aerobe with the respiratory metabolism closely resembling that of mammalian cells, amenable to both classical and molecular genetic techniques, having a long history of use as a producer of heterological proteins, possessing an ability to change its morphology (from yeast-like to true mycelium) in response to environmental conditions as an useful alternative in deciphering a role of mitochondrial dynamics and distribution in an yeast model of Alzheimer’s disease are suggested.","PeriodicalId":15012,"journal":{"name":"Journal of Alzheimers Disease & Parkinsonism","volume":"18 8 1","pages":"1-7"},"PeriodicalIF":0.0,"publicationDate":"2017-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83197424","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}
Pub Date : 2017-10-30DOI: 10.4172/2161-0460.1000393
F. Grinberg, E. Farrher, Xiang Gao, K. Konrad, I. Neuner, N. JonShah
Objective: Quantitative diffusion magnetic resonance imaging measures carry information about microstructural properties of the underlying tissue. Proper elucidation of their differences in healthy state and pathology, such as Alzheimer’s or Parkinson’s diseases, requires that these measures must be specific for the tissue or anatomic region of interest. However, they are often subjected to biases caused by partial volume effects and leading to erroneous analyses. The purpose of this work was to develop a novel tool allowing one to eliminate affected voxels from statistical analyses and, thus, improve accuracy of the derived measures and enhance reliability of between-group comparisons. Methods: In vivo diffusion kurtosis measurements were performed with a whole-body 3T Siemens MAGNETOM scanner for two differently aged groups of healthy volunteers. Mean values of typical diffusion tensor and kurtosis tensor metrics were estimated for 20 white matter anatomic regions. Relative differences between the group mean parameters in percentage and Cohen’s d values, as well as p-values of two-sided t-test analysis were evaluated before and after correction for partial volume effects. Results: We showed that using the tissue-specific features of diffusion kurtosis distributions allows one to reduce contamination of white matter structures by partial volume effects from neighbouring grey matter regions and cerebrospinal fluid. The performance of the developed method was demonstrated in the semi-automatic atlasbased comparison of two differently aged groups of healthy subjects showing that, after correction, the effect sizes of between-group differences in many regional diffusion indices become larger, whereas p-values of the t-tests decrease. Conclusion: Our work shows that excluding affected voxels from statistical analyses allows one to reduce confounding effects of mixing tissues and improves between-group comparisons. The proposed method is expected to be especially useful for detection of subtle between-group differences and longitudinal changes in studies of neurodegenerative pathologies and ageing associated with white matter atrophy.
{"title":"Novel Diffusion-Kurtosis-Informed Template Reduces Distortions due to Partial Volume Effects and Improves Statistical between-Group Comparisons","authors":"F. Grinberg, E. Farrher, Xiang Gao, K. Konrad, I. Neuner, N. JonShah","doi":"10.4172/2161-0460.1000393","DOIUrl":"https://doi.org/10.4172/2161-0460.1000393","url":null,"abstract":"Objective: Quantitative diffusion magnetic resonance imaging measures carry information about microstructural properties of the underlying tissue. Proper elucidation of their differences in healthy state and pathology, such as Alzheimer’s or Parkinson’s diseases, requires that these measures must be specific for the tissue or anatomic region of interest. However, they are often subjected to biases caused by partial volume effects and leading to erroneous analyses. The purpose of this work was to develop a novel tool allowing one to eliminate affected voxels from statistical analyses and, thus, improve accuracy of the derived measures and enhance reliability of between-group comparisons. Methods: In vivo diffusion kurtosis measurements were performed with a whole-body 3T Siemens MAGNETOM scanner for two differently aged groups of healthy volunteers. Mean values of typical diffusion tensor and kurtosis tensor metrics were estimated for 20 white matter anatomic regions. Relative differences between the group mean parameters in percentage and Cohen’s d values, as well as p-values of two-sided t-test analysis were evaluated before and after correction for partial volume effects. Results: We showed that using the tissue-specific features of diffusion kurtosis distributions allows one to reduce contamination of white matter structures by partial volume effects from neighbouring grey matter regions and cerebrospinal fluid. The performance of the developed method was demonstrated in the semi-automatic atlasbased comparison of two differently aged groups of healthy subjects showing that, after correction, the effect sizes of between-group differences in many regional diffusion indices become larger, whereas p-values of the t-tests decrease. Conclusion: Our work shows that excluding affected voxels from statistical analyses allows one to reduce confounding effects of mixing tissues and improves between-group comparisons. The proposed method is expected to be especially useful for detection of subtle between-group differences and longitudinal changes in studies of neurodegenerative pathologies and ageing associated with white matter atrophy.","PeriodicalId":15012,"journal":{"name":"Journal of Alzheimers Disease & Parkinsonism","volume":"37 1","pages":"1-11"},"PeriodicalIF":0.0,"publicationDate":"2017-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91137096","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}
Objective: Compensatory mechanisms are responsible for the clinical signs of suppression of neurodegeneration. Intervention into their mechanisms on an example of the ratio of excitatory and depressor synaptic responses will contribute to the development of therapeutic strategies.Methods: After 12-28 weeks (w) of experiment on the model of Alzheimer’s disease (AD), an activity of single neurons of hippocampus (H), Amygdala (Am) and, nucleus basalis of Meynert (NBM) to high frequency stimulation (HFS) of entorhinal cortex (EC) was recorded. The high frequency stimulation of H resulted in an activity of single neurons of the Am and NBM. By means of on-line selection and special mathematical analysis, tetanic potentiation (TP) and depression (TD) with further combination into posttetanic uni and multidirectional sequences, were revealed. In morpho- and histochemical study, the method of revelation of Сa2+- dependent phosphorylation was used.Results: After 12 weeks of experiment on the model of AD, a heavy TD of NBM and Аm neurons to HFS of H, as well as a weak (TD) in H and NBM neurons to HFS of EC were found. TP occurred by the activation of ЕС in the H (TP PTP) and in Am (TP PTD) neurons, equal to and above the norm in neurons of Am to HFS of H. In the neurons of NBM to HFS of EC, the weakest excitation to HFS of H was detected. In the neurons H to HFS of EC, Am and NBM to HFS of H, after 13-28 weeks, TD and tetanic excitation in all cases were low, which indicating on depletion of compensatory opportunities. Morpho- and histo-chemical changes of H, Am and NBM neurons on the model of AD were characterized by total tendency to structural-metabolic dysfunctions, with distortion of forms, central chromatolysis, presence of light ectopic nucleus with increased nucleolus, change reaction of neurofibrills, lack of reaction processes, accumulation of hyper phosphorylated entities and, presence of spaces with the lack of cellular reaction.Conclusion: The absence of expressed depression, presupposed by us as a protector in the present study, makes it necessary to involve pharmacological interventions with a view to its strengthening, and therefore is the subject of the next reports. Electrophysiological data have been confirmed morphologically.
{"title":"Morphofunctional Correlation of Excitatory and Depressor Synaptic Processes in Hippocampus, Amygdala and Basal Meynert Nucleus Neurons in Dynamics of Development of Alzheimer's Disease Model Induced by Aβ25-35","authors":"Sarkissian Js, Minasyan Al, Sahakyan Kt, Danielyan Mh, Stepanyan Hy, Poghossyan Mv, Sarkisian Vh","doi":"10.4172/2161-0460.1000391","DOIUrl":"https://doi.org/10.4172/2161-0460.1000391","url":null,"abstract":"Objective: Compensatory mechanisms are responsible for the clinical signs of suppression of neurodegeneration. Intervention into their mechanisms on an example of the ratio of excitatory and depressor synaptic responses will contribute to the development of therapeutic strategies.Methods: After 12-28 weeks (w) of experiment on the model of Alzheimer’s disease (AD), an activity of single neurons of hippocampus (H), Amygdala (Am) and, nucleus basalis of Meynert (NBM) to high frequency stimulation (HFS) of entorhinal cortex (EC) was recorded. The high frequency stimulation of H resulted in an activity of single neurons of the Am and NBM. By means of on-line selection and special mathematical analysis, tetanic potentiation (TP) and depression (TD) with further combination into posttetanic uni and multidirectional sequences, were revealed. In morpho- and histochemical study, the method of revelation of Сa2+- dependent phosphorylation was used.Results: After 12 weeks of experiment on the model of AD, a heavy TD of NBM and Аm neurons to HFS of H, as well as a weak (TD) in H and NBM neurons to HFS of EC were found. TP occurred by the activation of ЕС in the H (TP PTP) and in Am (TP PTD) neurons, equal to and above the norm in neurons of Am to HFS of H. In the neurons of NBM to HFS of EC, the weakest excitation to HFS of H was detected. In the neurons H to HFS of EC, Am and NBM to HFS of H, after 13-28 weeks, TD and tetanic excitation in all cases were low, which indicating on depletion of compensatory opportunities. Morpho- and histo-chemical changes of H, Am and NBM neurons on the model of AD were characterized by total tendency to structural-metabolic dysfunctions, with distortion of forms, central chromatolysis, presence of light ectopic nucleus with increased nucleolus, change reaction of neurofibrills, lack of reaction processes, accumulation of hyper phosphorylated entities and, presence of spaces with the lack of cellular reaction.Conclusion: The absence of expressed depression, presupposed by us as a protector in the present study, makes it necessary to involve pharmacological interventions with a view to its strengthening, and therefore is the subject of the next reports. Electrophysiological data have been confirmed morphologically.","PeriodicalId":15012,"journal":{"name":"Journal of Alzheimers Disease & Parkinsonism","volume":"20 1","pages":"1-16"},"PeriodicalIF":0.0,"publicationDate":"2017-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85362768","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}
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