Influence of Behavioral and Psychological Symptoms on Caregiver Burden for Different Types of Dementia: Clinical Experience in Lima, Peru.

INTRODUCTION: People caring for patients with dementia are prone to suffering from burden. Behavioral and psychological symptoms of dementia (BPSD) may have an impact on caregiver burden. In Latin American countries, there is a lack of research on caregiver burden. We aimed to determine which BPSD have the greatest impact on caregiver burden among Peruvian patients with dementia and to compare the effects of BPSD on caregiver burden across different types of dementia. METHODS: A cross-sectional study was conducted on 231 patients living with Alzheimer's dementia (AD), behavioral variant frontotemporal dementia (bvFTD), dementia with Lewy bodies (DLB), and vascular dementia (VD) and their caregivers who attended a Peruvian memory clinic. BPSD were assessed with the Neuropsychiatric Inventory (NPI). Caregiver burden was assessed with the Zarit Burden Inventory. We used analysis of variance to compare the AD, bvFTD, DLB, and VD groups. Correlations between Zarit Burden Inventory and NPI subscale scores were assessed with Spearman's correlation. RESULTS: DLB caregivers had significantly higher levels of burden than the other patient groups (p < 0.05) and higher total NPI scores than caregivers for other patient groups (p < 0.05). bvFTD caregivers had significantly higher total NPI scores than AD and VD caregivers (p < 0.05). Hallucinations, aberrant motor behavior, and apathy were the symptoms most significantly correlated with caregiver burden in those caring for DLB, bvFTD, and AD patients, respectively. CONCLUSION: Neuropsychiatric symptoms are higher in DLB caregivers. Hallucinations, aberrant motor behavior, and apathy are the main symptoms correlated with burden.

Frederic Lewy: how the two World Wars changed his life, work, and name / Frederic Lewy: como as duas Guerras Mundiais mudaram sua vida, trabalho e nome

Abstract In 1912, Friedrich Lewy described the inclusion bodies present in Parkinson disease and in Lewy body dementia. Throughout his life, Lewy fought in two wars - on opposite sides. He was born in Berlin in a Jewish family, and served in the German Army in World War I. In the following years, on many occasions he had to change his line of research due to Nazi persecution. Lewy became a naturalized American, changed his name to Frederic Henry Lewey, and served in the US Army as a lieutenant colonel. Lewy died in 1950 and never used the famous eponym in his papers.

Resumo Em 1912, Friedrich Lewy descreveu os corpos de inclusão presentes na doença de Parkinson e na demência com corpos de Lewy. Ao longo sua vida, Lewy lutou em duas guerras, em lados opostos. Ele nasceu em Berlin em uma família de origem judaica e serviu no Exército alemão na Primeira Guerra Mundial. Nos anos seguintes, passou muitas vezes teve de mudar sua linha de pesquisa devido à perseguição Nazista. Lewy naturalizou-se americano, mudou seu nome para Frederic Henry Lewey, e serviu no Exército americano como tenente-coronel. Lewy morreu em 1950 e nunca usou o famoso epônimo em seus artigos.

Diagnostic criteria in dementing illness. What's new? / Criterios diagnósticos en la enfermedad demencial ¿Qué hay de nuevo?

The spectrum of neurodegenerative diseases that primarily affect cognition and behaviorspreads from asymptomatic preclinical disease to very mild cognitive impairment to frank dementia. Alzheimer's disease (AD) is the most common cause of a decline in cognitive ability. Also, it is a devastating condition that affects patients and their entirefamilies of caregivers, exacting tremendous financial hardships. Diagnosis may be complicated by other forms of dementia that have symptoms and pathologies similar to AD. Knowing the key features and pathology of each type of dementia can help in the accurate diagnosis of patients, so they will receive the treatment and support services appropriate for their condition and maintain the highest possible functioning in daily life and quality of life. Differentiate, based on clinical criteria, neuropathology, and biomarkers, AD and its atypical variants from other common dementias including Dementia with Lewy Bodies, Vascular Cognitive Impairment, Frontotemporal Degeneration, and less frequent cognitive disorders. The importance of getting an accurate and early diagnosis of dementiais now increasingly significant to make important decisions about treatment, support, and care. Nonpharmacological as well as pharmacological interventions should be initiated once the diagnosis is obtained. Biochemical markers to identify Alzheimer's disease play a central role in the new diagnostic criteria for the disease and in the recent biological definition of AD. This review article presents up-to-date data regarding the recent diagnostic criteria of Alzheimer´s disease and related disorders, emphasizing its usefulness in routine clinical practice.

El espectro de enfermedades neurodegenerativas que afectan principalmente a la cognición y el comportamiento abarca desde la enfermedad preclínica asintomática hasta el deterioro cognitivo muy leve y la demencia franca. La enfermedad de Alzheimer (EA) es la causa más común de deterioro de la capacidad cognitiva. Es una enfermedad devastadora que afecta a los pacientes y a toda su familia de cuidadores, lo que supone enormes dificultades socioeconómicas y psicoemocionales. El diagnóstico puede complicarse debido a otras formas de demencia que presentan síntomas y patologías similares a la EA. Los marcadores bioquímicos para identificar la enfermedad de Alzheimer desempeñan un papel central en los nuevos criterios diagnósticos de la enfermedad y en la reciente definición biológica de la EA. Conocer las características claves y la patología de cada tipo de demencia puede ayudar en el diagnóstico preciso de los pacientes, a fin de que reciban el tratamiento y los servicios de apoyo adecuados a su condición y mantengan el mayor funcionamiento posible en la vida diaria y la calidad de vida. Por lo tanto es prioritario diferenciar, basándose en criterios clínicos, neuropatología y biomarcadores, la EA y sus variantes atípicas de otras demencias comunes como el Deterioro Cognitivo Vascular, la Degeneración Fronto- temporal entre otras, y los trastornos cognitivos menos frecuentes. Este artículo de revisión presenta datos actualizados relativos a los recientes criterios diagnósticos de algunas formas de demencia haciendo hincapié en su utilidad en la práctica clínica habitual. Se exponen los criterios de EA, de Demencia Vascular (DV), de la demencia Fronto-temporal (DFT) y de una forma rara de demencia, descripta en los últimos años, que se evidencia en pacientes muy añosos con un perfil similar a la EA. Se trata de la encefalopatía predominantemente límbica por tdp- 43 relacionada a la edad (LATE).

Assistência de enfermagem em pacientes com Demência do Corpo de Lewy / Nursing assistance in patients with Lewy's Body Dementia

Objetivo: Investigar sobre a assistência de Enfermagem a pacientes com Demência do Corpo de Lewy. Método: Revisão integrativa da literatura, pela busca nas bases de dados, entre os anos de 2009 a 2021, utilizando os descritores: Doença por corpos de Lewy, Doença de Alzheimer, Doença de Parkinson, Assistência de Enfermagem. Resultado: A Demência do Corpo de Lewy é uma doença de difícil diagnóstico, por causa das semelhanças com as Doenças de Alzheimer e Parkinson, seu tratamento é baseado nessas patologias, não seguindo protocolos específicos da doença. A enfermagem tem por função principalmente orientar a família e oferecer uma assistência integral tanto para o paciente, quanto para o cuidador. Conclusão: É necessária, a realização de mais estudos, para entender como assistir um paciente diagnosticado com esta patologia adequadamente, dando suporte para um cuidado de enfermagem mais científico e integral, estabelecendo rotinas, promoveno assim qualidade de vida ao paciente e sua família.(AU)

Objective: To investigate Nursing care for patients with Lewy Body Dementia. Method: Integrative literature review, using the Scielo database, between 2009 and 2021, using the descriptors: Lewy body disease, Alzheimer's disease, Parkinson's disease, Nursing care. Result: Lewy Body Dementia is a disease that is difficult to diagnose, because of the similarities with Alzheimer's and Parkinson's Diseases, its treatment is based on these pathologies, not following disease-specific protocols. Nursing's main function is to guide the family and offer comprehensive care for both the patient and the caregiver. Conclusion: Further studies are needed to understand how to properly care for a patient diagnosed with this pathology, supporting a more scientific and comprehensive nursing care, establishing routines, thus promoting quality of life for patients and their families.(AU)

Objetivo: Investigar el cuidado de Enfermería a pacientes con Demencia con Cuerpos de Lewy. Método: Revisión integrativa de la literatura, utilizando la base de datos Scielo, entre 2009 y 2021, utilizando los descriptores: Enfermedad de cuerpos de Lewy, Enfermedad de Alzheimer, Enfermedad de Parkinson, Cuidados de enfermería. Resultado: La Demencia con Cuerpos de Lewy es una enfermedad de difícil diagnóstico, debido a las similitudes con el Alzheimer y el Parkinson, su tratamiento se basa en estas patologías, no siguiendo protocolos específicos de la enfermedad. La función principal de enfermería es orientar a la familia y ofrecer una atención integral tanto al paciente como al cuidador. Conclusión: Se necesitan más estudios para comprender cómo cuidar adecuadamente a un paciente diagnosticado con esta patología, apoyando un cuidado de enfermería más científico e integral, estableciendo rutinas, promoviendo así la calidad de vida de los pacientes y sus familias.(AU)

PPARs and Their Neuroprotective Effects in Parkinson's Disease: A Novel Therapeutic Approach in α-Synucleinopathy?

Parkinson's disease (PD) is the most common α-synucleinopathy worldwide. The pathognomonic hallmark of PD is the misfolding and propagation of the α-synuclein (α-syn) protein, observed in post-mortem histopathology. It has been hypothesized that α-synucleinopathy triggers oxidative stress, mitochondrial dysfunction, neuroinflammation, and synaptic dysfunction, leading to neurodegeneration. To this date, there are no disease-modifying drugs that generate neuroprotection against these neuropathological events and especially against α-synucleinopathy. Growing evidence suggests that peroxisome proliferator-activated receptor (PPAR) agonists confer neuroprotective effects in PD, however, whether they also confer an anti-α-synucleinopathy effect is unknown. Here we analyze the reported therapeutic effects of PPARs, specifically the gamma isoform (PPARγ), in preclinical PD animal models and clinical trials for PD, and we suggest possible anti-α-synucleinopathy mechanisms acting downstream from these receptors. Elucidating the neuroprotective mechanisms of PPARs through preclinical models that mimic PD as closely as possible will facilitate the execution of better clinical trials for disease-modifying drugs in PD.

Rotenone-Induced Model of Parkinson's Disease: Beyond Mitochondrial Complex I Inhibition.

Parkinson's disease (PD) is usually diagnosed through motor symptoms that make the patient incapable of carrying out daily activities; however, numerous non-motor symptoms include olfactory disturbances, constipation, depression, excessive daytime sleepiness, and rapid eye movement at sleep; they begin years before motor symptoms. Therefore, several experimental models have been studied to reproduce several PD functional and neurochemical characteristics; however, no model mimics all the PD motor and non-motor symptoms to date, which becomes a limitation for PD study. It has become increasingly relevant to find ways to study the disease from its slowly progressive nature. The experimental models most frequently used to reproduce PD are based on administering toxic chemical compounds, which aim to imitate dopamine deficiency. The most used toxic compounds to model PD have been 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA), which inhibit the complex I of the electron transport chain but have some limitations. Another toxic compound that has drawn attention recently is rotenone, the classical inhibitor of mitochondrial complex I. Rotenone triggers the progressive death of dopaminergic neurons and α-synuclein inclusions formation in rats; also, rotenone induces microtubule destabilization. This review presents information about the experimental model of PD induced by rotenone, emphasizing its molecular characteristics beyond the inhibition of mitochondrial complex I.

Diagnosis and management of Parkinson's disease dementia and dementia with Lewy bodies: recommendations of the Scientific Department of Cognitive Neurology and Aging of the Brazilian Academy of Neurology.

Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) represent the second most common type of degenerative dementia in patients aged 65 years and older, leading to progressive cognitive dysfunction and impaired quality of life. This study aims to provide a consensus based on a systematic Brazilian literature review and a comprehensive international review concerning PDD and DLB. Moreover, we sought to report on and give recommendations about the best diagnostic approaches focusing on primary and secondary care. Based on the available data, we recommend clinicians to apply at least one brief global cognitive instrument to assess PDD, such as the Mini-Mental State Examination and preferably the Montreal Cognitive Assessment and the Addenbrooke's Cognitive Examination-Revised. Validated instruments to accurately assess functional abilities in Brazilian PD patients are still incipient. Further studies should focus on biomarkers with Brazilian cohorts.

A demência da doença de Parkinson (DDP) e a demência com corpos de Lewy (DCL) representam a segunda causa mais comum de demência neurodegenerativa em pessoas com mais de 65 anos, ocasionando progressivo declínio cognitivo e comprometimento da qualidade de vida. O presente estudo tem como objetivo prover um consenso de especialistas sobre a DDP e DCL, baseado em revisão sistemática da literatura brasileira e revisão não-sistemática de literatura internacional. Ademais, tal estudo visa promover informação e conceder recomendações sobre abordagem diagnóstica, com foco nos níveis de atenção primária e secundária em saúde. Com base nos dados disponíveis, recomendamos que os profissionais realizem pelo menos um breve instrumento cognitivo global, como o Mini-Exame do Estado Mental, contudo de preferência optem pela Avaliação Cognitiva de Montreal e o Exame Cognitivo de Addenbrooke-Revisado. Observa-se uma carência de instrumentos validados para a avaliação precisa das habilidades funcionais em pacientes brasileiros com DDP e DCL. Além disso, mais estudos focando em biomarcadores com coortes brasileiras também são necessários.

Diagnóstico e manejo da demência da doença de Parkinson e demência com corpos de Lewy: recomendações do Departamento Científico de Neurologia Cognitiva e do Envelhecimento da Academia Brasileira de Neurologia / Diagnosis and management of Parkinson's disease dementia and dementia with Lewy bodies: recommendations of the Scientific Department of Cognitive Neurology and Aging of the Brazilian Academy of Neurology

RESUMO A demência da doença de Parkinson (DDP) e a demência com corpos de Lewy (DCL) representam a segunda causa mais comum de demência neurodegenerativa em pessoas com mais de 65 anos, ocasionando progressivo declínio cognitivo e comprometimento da qualidade de vida. O presente estudo tem como objetivo prover um consenso de especialistas sobre a DDP e DCL, baseado em revisão sistemática da literatura brasileira e revisão não-sistemática de literatura internacional. Ademais, tal estudo visa promover informação e conceder recomendações sobre abordagem diagnóstica, com foco nos níveis de atenção primária e secundária em saúde. Com base nos dados disponíveis, recomendamos que os profissionais realizem pelo menos um breve instrumento cognitivo global, como o Mini-Exame do Estado Mental, contudo de preferência optem pela Avaliação Cognitiva de Montreal e o Exame Cognitivo de Addenbrooke-Revisado. Observa-se uma carência de instrumentos validados para a avaliação precisa das habilidades funcionais em pacientes brasileiros com DDP e DCL. Além disso, mais estudos focando em biomarcadores com coortes brasileiras também são necessários.

ABSTRACT Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) represent the second most common type of degenerative dementia in patients aged 65 years and older, leading to progressive cognitive dysfunction and impaired quality of life. This study aims to provide a consensus based on a systematic Brazilian literature review and a comprehensive international review concerning PDD and DLB. Moreover, we sought to report on and give recommendations about the best diagnostic approaches focusing on primary and secondary care. Based on the available data, we recommend clinicians to apply at least one brief global cognitive instrument to assess PDD, such as the Mini-Mental State Examination and preferably the Montreal Cognitive Assessment and the Addenbrooke's Cognitive Examination-Revised. Validated instruments to accurately assess functional abilities in Brazilian PD patients are still incipient. Further studies should focus on biomarkers with Brazilian cohorts.

Case Report: Depression × dementia with Lewy bodies in the elderly: The importance of differential diagnosis.

Background: Dementia is a clinical syndrome which is more common in elderly people. Dementia with Lewy bodies (LBD) is not so rare in elderly people, with cognitive impairment in about 30% over age 65. The clinical picture is characterized by fluctuation in cognitive functions, recurrent, well-formed, detailed visual hallucinations, and Parkinsonism, with rigidity, tremor, bradykinesia, and slurred speech. Case presentation: We present a case report of LBD in a 73-year-old retired teacher, which a initial wrong diagnosis of refractory depression for at least 3 years. We also conduct a review of recent works on theme. Conclusion: LBD diagnosis can be neglected for years, with a legal and clinical issues to patients and their families. Detailed medical research, including differential diagnosis, are very necessary on those cases, specially when they are called refractory. We encourage new research and adequate clinical training to prevent damage.

An Update on the Critical Role of α-Synuclein in Parkinson's Disease and Other Synucleinopathies: from Tissue to Cellular and Molecular Levels.

The aggregation of alpha-synuclein (α-Syn) plays a critical role in the development of Parkinson's disease (PD) and other synucleinopathies. α-Syn, which is encoded by the SNCA gene, is a lysine-rich soluble amphipathic protein normally expressed in neurons. Located in the cytosolic domain, this protein has the ability to remodel itself in plasma membranes, where it assumes an alpha-helix conformation. However, the protein can also adopt another conformation rich in cross-beta sheets, undergoing mutations and post-translational modifications, then leading the protein to an unusual aggregation in the form of Lewy bodies (LB), which are cytoplasmic inclusions constituted predominantly by α-Syn. Pathogenic mechanisms affecting the structural and functional stability of α-Syn - such as endoplasmic reticulum stress, Golgi complex fragmentation, disfunctional protein degradation systems, aberrant interactions with mitochondrial membranes and nuclear DNA, altered cytoskeleton dynamics, disrupted neuronal plasmatic membrane, dysfunctional vesicular transport, and formation of extracellular toxic aggregates - contribute all to the pathogenic progression of PD and synucleinopathies. In this review, we describe the collective knowledge on this topic and provide an update on the critical role of α-Syn aggregates, both at the cellular and molecular levels, in the deregulation of organelles affecting the cellular homeostasis and leading to neuronal cell death in PD and other synucleinopathies.

Active lifestyle enhances protein expression profile in subjects with Lewy body pathology.

Clinical trials of the effects of physical activity have reported improvements in symptoms and quality of life in patients with Parkinson's disease (PD). Additionally, morphological brain changes after exercising were reported in PD animal models. However, these lifestyle-related changes were not evaluated in postmortem brain tissue. OBJECTIVE: We aimed to evaluate, by immunohistochemistry, astrocytes, tyrosine hydroxylase (TH) and structural proteins expression (neurofilaments and microtubules - MAP2) changes in postmortem brain samples of individuals with Lewy body pathology. METHODS: Braak PD stage≥III samples, classified by neuropathology analysis, from The Biobank for Aging Studies were classified into active (n=12) and non-active (n=12) groups, according to physical activity lifestyle, and paired by age, sex and Braak staging. Substantia nigra and basal ganglia were evaluated. RESULTS: Groups were not different in terms of age or gender and had similar PD neuropathological burden (p=1.00). We observed higher TH expression in the active group in the substantia nigra and the basal ganglia (p=0.04). Astrocytes was greater in the non-active subjects in the midbrain (p=0.03) and basal ganglia (p=0.0004). MAP2 levels were higher for non-active participants in the basal ganglia (p=0.003) and similar between groups in the substantia nigra (p=0.46). Neurofilament levels for non-active participants were higher in the substantia nigra (p=0.006) but not in the basal ganglia (p=0.24). CONCLUSION: Active lifestyle seems to promote positive effects on brain by maintaining dopamine synthesis and structural protein expression in the nigrostriatal system and decrease astrogliosis in subjects with the same PD neuropathology burden.

Estudos dos efeitos da atividade física relataram melhora nos sintomas e na qualidade de vida de pacientes com doença de Parkinson (DP). Além disso, alterações morfológicas do cérebro após o exercício físico foram relatadas em modelos animais da DP. No entanto, essas mudanças relacionadas ao estilo de vida não foram avaliadas em tecido cerebral post-mortem. OBJETIVO: Avaliar a expressão de astrócitos, tirosina hidroxilase (TH) e a expressão de proteínas estruturais (neurofilamentos e microtúbulos ­ MAP2) por imuno-histoquímica, em amostras cerebrais post-mortem de indivíduos com corpos de Lewy. MÉTODOS: Amostras com estágio de Braak para DP≥III, classificação neuropatológica, fornecidas pelo biobanco de estudos do envelhecimento foram classificadas em grupos ativos (n=12) e não ativos (n=12), de acordo com o estilo de vida (atividade física), e pareados por idade, sexo e estadiamento de Braak. Analisou-se a substância negra e gânglios da base. RESULTADOS: Idade, sexo e classificação para DP foram semelhantes (p=1,00). Observou-se maior expressão de TH no grupo ativo (p=0,04). Amostras de não ativos revelaram maior expressão de astrócitos no mesencéfalo (p=0,03) e nos gânglios da base (p=0,0004); MAP2 nos gânglios da base (p=0,003); os níveis de neurofilamentos foram maiores na substância negra (p=0,006). CONCLUSÃO: O estilo de vida ativo parece promover efeitos positivos no cérebro, mantendo a síntese de dopamina e a expressão estrutural de proteínas no sistema nigrostriatal e com diminuição da ativação de astrócitos em indivíduos com a mesma classificação neuropatológica para a DP.

Active lifestyle enhances protein expression profile in subjects with Lewy body pathology / O estilo de vida ativo melhora o perfil de expressão de proteínas em indivíduos com a patologia de corpos de lewy

ABSTRACT. Clinical trials of the effects of physical activity have reported improvements in symptoms and quality of life in patients with Parkinson's disease (PD). Additionally, morphological brain changes after exercising were reported in PD animal models. However, these lifestyle-related changes were not evaluated in postmortem brain tissue. Objective: We aimed to evaluate, by immunohistochemistry, astrocytes, tyrosine hydroxylase (TH) and structural proteins expression (neurofilaments and microtubules — MAP2) changes in postmortem brain samples of individuals with Lewy body pathology. Methods: Braak PD stage≥III samples, classified by neuropathology analysis, from The Biobank for Aging Studies were classified into active (n=12) and non-active (n=12) groups, according to physical activity lifestyle, and paired by age, sex and Braak staging. Substantia nigra and basal ganglia were evaluated. Results: Groups were not different in terms of age or gender and had similar PD neuropathological burden (p=1.00). We observed higher TH expression in the active group in the substantia nigra and the basal ganglia (p=0.04). Astrocytes was greater in the non-active subjects in the midbrain (p=0.03) and basal ganglia (p=0.0004). MAP2 levels were higher for non-active participants in the basal ganglia (p=0.003) and similar between groups in the substantia nigra (p=0.46). Neurofilament levels for non-active participants were higher in the substantia nigra (p=0.006) but not in the basal ganglia (p=0.24). Conclusion: Active lifestyle seems to promote positive effects on brain by maintaining dopamine synthesis and structural protein expression in the nigrostriatal system and decrease astrogliosis in subjects with the same PD neuropathology burden.

RESUMO. Estudos dos efeitos da atividade física relataram melhora nos sintomas e na qualidade de vida de pacientes com doença de Parkinson (DP). Além disso, alterações morfológicas do cérebro após o exercício físico foram relatadas em modelos animais da DP. No entanto, essas mudanças relacionadas ao estilo de vida não foram avaliadas em tecido cerebral post-mortem. Objetivo: Avaliar a expressão de astrócitos, tirosina hidroxilase (TH) e a expressão de proteínas estruturais (neurofilamentos e microtúbulos — MAP2) por imuno-histoquímica, em amostras cerebrais post-mortem de indivíduos com corpos de Lewy. Métodos: Amostras com estágio de Braak para DP≥III, classificação neuropatológica, fornecidas pelo biobanco de estudos do envelhecimento foram classificadas em grupos ativos (n=12) e não ativos (n=12), de acordo com o estilo de vida (atividade física), e pareados por idade, sexo e estadiamento de Braak. Analisou-se a substância negra e gânglios da base. Resultados: Idade, sexo e classificação para DP foram semelhantes (p=1,00). Observou-se maior expressão de TH no grupo ativo (p=0,04). Amostras de não ativos revelaram maior expressão de astrócitos no mesencéfalo (p=0,03) e nos gânglios da base (p=0,0004); MAP2 nos gânglios da base (p=0,003); os níveis de neurofilamentos foram maiores na substância negra (p=0,006). Conclusão: O estilo de vida ativo parece promover efeitos positivos no cérebro, mantendo a síntese de dopamina e a expressão estrutural de proteínas no sistema nigrostriatal e com diminuição da ativação de astrócitos em indivíduos com a mesma classificação neuropatológica para a DP.

Tumor necrosis factor receptor-associated factor 6 interaction with alpha-synuclein enhances cell death through the Nuclear Factor-kB pathway.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disease characterized by intracellular inclusions named Lewy bodies (LB), and alpha-synuclein (asyn) is the major component of these protein aggregates. The precise physiological and pathological roles of asyn are not fully understood. Nevertheless, asyn present in LB is ubiquitinated but fails to reach the 26S proteasome. The mutation A30 P is related to an aggressive and early-onset form of PD. Tumor necrosis factor receptor-associated factor 6 (TRAF6) is an E3 ubiquitin ligase, and it interacts and ubiquitinates the asyn in atypical chains (lysine K6, K27, K29, and K33). Methods: Here, we investigated the role of TRAF6 interaction with asyn and the involvement of nuclear factor κB (NF-κB), a key transcription factor in pro-inflammatory signaling pathway activation. RESULTS AND CONCLUSION: We demonstrated that TRAF6 binds to both WT and the mutant form A30 P asyn in an SH-SY5Y cell model. Additionally, the interaction between TRAF6 and WT asyn induced an increase in the activation of NF-κB, leading to changes in TNF, IL-1ß and IL-10 levels and culminating in reduced cell viability. Interestingly, the activation of NF-κB and gene regulation were not found in A30 P asyn. These data point to a novel role of TRAF6 in the pathophysiology of PD.

A multi-faceted genotoxic network of alpha-synuclein in the nucleus and mitochondria of dopaminergic neurons in Parkinson's disease: Emerging concepts and challenges.

α-Synuclein is a hallmark amyloidogenic protein component of the Lewy bodies (LBs) present in dopaminergic neurons affected by Parkinson's disease (PD). Despite an enormous increase in emerging knowledge, the mechanism(s) of α-synuclein neurobiology and crosstalk among pathological events that are critical for PD progression remains enigmatic, creating a roadblock for effective intervention strategies. One confounding question is about the potential link between α-synuclein toxicity and genome instability in PD. We previously reported that pro-oxidant metal ions, together with reactive oxygen species (ROS), act as a "double whammy" in dopaminergic neurons by not only inducing genome damage but also inhibiting their repair. Our recent studies identified a direct role for chromatin-bound, oxidized α-synuclein in the induction of DNA strand breaks, which raised the question of a paradoxical role for α-synuclein's DNA binding in neuroprotection versus neurotoxicity. Furthermore, recent advances in our understanding of α-synuclein mediated mitochondrial dysfunction warrants revisiting the topics of α-synuclein pathophysiology in order to devise and assess the efficacy of α-synuclein-targeted interventions. In this review article, we discuss the multi-faceted neurotoxic role of α-synuclein in the nucleus and mitochondria with a particular emphasis on the role of α-synuclein in DNA damage/repair defects. We utilized a protein-DNA binding simulation to identify potential residues in α-synuclein that could mediate its binding to DNA and may be critical for its genotoxic functions. These emerging insights and paradigms may guide new drug targets and therapeutic modalities.

Alpha-Synuclein Physiology and Pathology: A Perspective on Cellular Structures and Organelles.

Alpha-synuclein (α-syn) is localized in cellular organelles of most neurons, but many of its physiological functions are only partially understood. α-syn accumulation is associated with Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy as well as other synucleinopathies; however, the exact pathomechanisms that underlie these neurodegenerative diseases remain elusive. In this review, we describe what is known about α-syn function and pathophysiological changes in different cellular structures and organelles, including what is known about its behavior as a prion-like protein. We summarize current knowledge of α-syn and its pathological forms, covering its effect on each organelle, including aggregation and toxicity in different model systems, with special interest on the mitochondria due to its relevance during the apoptotic process of dopaminergic neurons. Moreover, we explore the effect that α-syn exerts by interacting with chromatin remodeling proteins that add or remove histone marks, up-regulate its own expression, and resume the impairment that α-syn induces in vesicular traffic by interacting with the endoplasmic reticulum. We then recapitulate the events that lead to Golgi apparatus fragmentation, caused by the presence of α-syn. Finally, we report the recent findings about the accumulation of α-syn, indirectly produced by the endolysosomal system. In conclusion, many important steps into the understanding of α-syn have been made using in vivo and in vitro models; however, the time is right to start integrating observational studies with mechanistic models of α-syn interactions, in order to look at a more complete picture of the pathophysiological processes underlying α-synucleinopathies.

Demencia Por Cuerpos De Lewy, Un Reto Diagnóstico / Dementia With Lewy Bodies, A Diagnostic Challenge

Resumen La Demencia por cuerpos de Lewy es una enfermedad neurodegenerativa de etiología desconocida, corresponde a la segunda causa de demencia a partir de la sexta década de vida; su diagnóstico es un reto, debido a que ciertos de los signos y síntomas que presenta son típicos de la Enfermedad de Parkinson y la Enfermedad de Alzheimer. El siguiente reporte de caso es de los primeros en documentar un paciente con Demencia por cuerpos de Lewy en el Ecuador. Se expone un caso con Demencia por cuerpos de Lewy con el fin de plasmar la dificultad diagnóstica que genera esta patología y describir las características principales que la diferencian de otros síndromes demenciales, destacadas en los criterios recientemente actualizados por el Consorcio de Demencia por Cuerpos de Lewy. Un meticuloso examen neurológico y valoración neuropsicológica fueron ejes en el estudio y pronóstico del paciente que presentamos. La Demencia por cuerpos de Lewy requiere un diagnóstico minucioso, debido al desafío que origina su reconocimiento precoz; los criterios descritos aceleraron su reconocimiento gracias a la actualización de las recomendaciones sobre el diagnóstico clínico de Demencia por cuerpos de Lewy.

Abstract Dementia with Lewy bodies is a neurodegenerative disease of unknown etiology, it is the second cause of dementia of the sixth decade of life; Its diagnosis is a challenge, because certain signs and symptoms that it presents are typical of Parkinson's Disease and Alzheimer's Disease. The following case report is one of the few documented patients with Dementia with Lewy bodies in Ecuador. We report this in order to state the diagnostic difficulty that this pathology generates and describe the main characteristics that differentiate it from other dementia syndromes, highlighted in the recently updated criteria by the Consortium of Dementia with Lewy bodies. A meticulous neurological examination and neuropsychological assessment were essential in the study and prognosis of the patient. Dementia with Lewy bodies requires a thorough diagnosis, due to the challenge that originates its early recognition; the criteria described accelerated their recognition due the update of the recommendations on the clinical diagnosis of Dementia with Lewy bodies.

Propagation of alpha-synuclein pathology from the olfactory bulb: possible role in the pathogenesis of dementia with Lewy bodies.

Olfactory limbic structures, like the amygdala, the entorhinal, and the piriform cortices, are closely involved in cognitive processes. Thus, besides olfactory dysfunctions, it is conceivable that the compromise of these structures can lead to cognitive impairment. The olfactory bulb is affected by alpha-synuclein pathology in almost all cases of both Parkinson's disease and dementia with Lewy bodies. The clinical distinction between these disorders relies on the timing in the appearance of dementia in relationship to motor symptoms. Typically, it occurs late in the course of Parkinson's disease, and within the first year in dementia with Lewy bodies. The close anatomical proximity of the olfactory bulb with limbic regions, together with the early occurrence of cognitive impairment that is observed in dementia with Lewy bodies, raise the question whether the propagation of alpha-synuclein pathology in this condition might originate in the olfactory bulb, spreading from there to other limbic structures, and thereby reaching the associative neocortex. This review will describe the anatomical basis of the olfactory system and discuss the evidence of potential spreading pathways from the olfactory bulb that could support the presence of early dementia in the setting of Lewy body disorders.

Lewy and his inclusion bodies: Discovery and rejection.

Fritz Jacob Heinrich Lewy described the pathology of Paralysis agitans [Parkinson disease] and was the first to identify eosinophilic inclusion bodies in neurons of certain brain nuclei, later known as Lewy bodies, the pathological signature of the Lewy body diseases. In 1912, he published his seminal study, followed soon after by an update paper, and 10 years later, in 1923, by his voluminous book, where he exhaustively described the subject. The publication provided extensive information on the pathology of Paralysis agitans, and the entirely novel finding of eosinophilic inclusion bodies, which would become widely recognized and debated in the future. His discovery was acknowledged by important researchers who even named the structure after him. However, after his last publication on the issue, inexplicably, he never mentioned his histopathological discovery again. Despite several hypotheses, the reasons that led him to neglect (reject) the structure which he so preeminently described have remained elusive.

Fritz Jacob Heinrich Lewy descreveu a patologia da Paralysis agitans [doença de Parkinson] e identificou pela primeira vez corpos de inclusão eosinófílos em neurônios de certos núcleos cerebrais, conhecidos mais tarde como corpos de Lewy, assinatura patológica das doenças dos corpos de Lewy. Ele divulgou em 1912 seu trabalho seminal, seguido logo por um artigo de atualização e 10 anos depois, em 1923, seu volumoso livro onde detalhou exaustivamente o assunto. Ali ele trouxe extensa informação sobre a patologia da Paralysis agitans e um achado inteiramente novo, os corpos de inclusão eosinófilos, que seriam valorizados e largamente debatidos no futuro. Seu achado foi reconhecido por importantes pesquisadores que até designaram essa estrutura com seu nome. Entretanto, após sua última publicação sobre o assunto, inexplicavelmente , ele nunca mais mencionou sua descoberta histopatológica. Apesar de diversas hipóteses, a razão que o levou negligenciar (rejeitar) a estrutura, que teve a primazia de descrever, permaneceu desconhecida.

Lafora and Trétiakoff: the naming of the inclusion bodies discovered by Lewy / Lafora e Trétiakoff: a denominação dos corpos de inclusão descobertos por Lewy

ABSTRACT Fritz Heinrich Jakob Lewy described, for the first time, in 1912, novel peculiar inclusions in neurons of certain brain nuclei in patients with Paralysis agitans, and compared his finding to the amyloid bodies described by Lafora one year before. Gonzalo Rodriguez Lafora studied one patient with Paralysis agitans, in 1913, and recognized, described, and depicted structures identical to those previously reported by Lewy. He was the first to acknowledge Lewy's finding, and also the first to name such inclusions after the discoverer - cuerpos intracelulares de Lewy (Lewy bodies). Konstantin Nikolaevich Trétiakoff named the inclusions he found in neurons of the substantia nigra of patients with Parkinson's disease as corps de Lewy (Lewy bodies), in 1919. Trétiakoff has unanimously received the credit for the eponym. However, Lafora's earlier description should make him deserving of the authorship of the eponym.

RESUMO Fritz Heinrich Jakob Lewy descreveu pela primeira vez, em 1912, inclusões singulares inéditas em neurônios de certos núcleos do cérebro em casos de Paralysis agitans e comparou seu achado aos corpos amilóides, como descrito por Lafora um ano antes. Gonzalo Rodriguez Lafora estudou um caso de Paralysis agitans, em 1913,e reconheceu, descreveu e representou estruturas idênticas às recentemente relatadas por Lewy. Foi o primeiro a reconhecer o achado de Lewy e também o primeiro a denominar tais inclusões segundo seu descobridor - cuerpos intracelulares de Lewy (corpos de Lewy). Konstantin Nikolaevich Tretiakoff designou as inclusões que encontrou em neurônios da substantia nigra em casos de doença de Parkinson de corps de Lewy (corpos de Lewy), em 1919. Ele recebeu o crédito pelo epônimo de modo unânime. Entretanto, a descrição anterior de Lafora deveria fazê-lo merecedor da autoria do epônimo.