Assessing Independence in Activities of Daily Living and Quality of Life in Patients with Dementia with Lewy Bodies.

Knowledge of performance in activities of daily living and quality of life is important for management decisions and research endpoints. The use of harmonized scales is essential for objective assessment of both caregivers and patients with dementia with Lewy bodies. Functionality and quality of life are more impaired in dementia with Lewy bodies than in Alzheimer's disease, mostly due to higher prevalence of behavioral symptoms and motor manifestations in dementia with Lewy bodies. More longitudinal studies are required to assess if causality mediates the associations of clinical features with functional independence and worsened quality of life in these patients.

Is Montreal Cognitive Assessment a valuable test for the differentiation of Alzheimer's disease, frontotemporal dementia, dementia with Lewy body, and vascular dementia?

Dementia is one of the growing diseases in the world and has different types based on its definition. The Montreal Cognitive Assessment (MoCA) test has been employed to screen patients with dementia, cognitive impairment, and disruption of daily activities. Objective: This study examined the diagnostic value of the total MoCA score and its subscores in differentiating Alzheimer's disease (AD), frontotemporal dementia (FTD), dementia with Lewy body (DLB), and vascular dementia (VaD). Methods: A total of 241 patients (AD=110, FTD=90, DLB=28, and VaD=13) and 59 healthy persons, who were referred to a dementia clinic with memory impairment in Firoozgar Hospital, were included in this study. MoCA tests were performed in all patients and normal persons. Results: By using the receiver operating characteristic (ROC) curve and measuring the area under the curve (AUC) for the total MoCA score in each group, AUC was 0.616, 0.681, 0.6117, and 0.583 for differentiating AD, FTD, DLB, and VaD patients, respectively. Among the groups, just the VaD group showed no significant usefulness in using the total MoCA score to differentiate it. To compare MoCA subscores, AD patients had higher scores in digit span, literal fluency, and abstraction but lower delayed recall scores compared with FTD patients. Conclusion: The total MoCA score and its subscores could not differentiate people with different types of dementia in the setting of screening.

A demência é uma das doenças que mais cresce no mundo e possui diferentes tipos de acordo com sua definição. O teste de Avaliação Cognitiva de Montreal (Montreal Cognitive Assessment ­ MoCA) tem sido empregado para a triagem de pacientes com demência, comprometimento cognitivo e perturbação das atividades diárias. Objetivo: Este estudo examinou o valor diagnóstico da pontuação total do MoCA e seus subescores na diferenciação entre doença de Alzheimer (DA), demência frontotempotal (DFT), demência com corpos de Lewy (DCL) e demência vascular (DV). Métodos: Este estudo incluiu 241 pacientes (DA=110, DFT=90, DCL=28 e DV=13) e 59 pessoas saudáveis, encaminhados à clínica de demência com comprometimento de memória no Hospital Firoozgar. O teste MoCA foi realizado em todos os pacientes e pessoas normais. Resultados: Usando a curva característica de operação do receptor (ROC) e medindo a área sob a curva (AUC) para a pontuação total do MoCA em cada grupo, a AUC foi de 0,616, 0,681, 0,6117 e 0,583 para diferenciar pacientes com DA, DFT, DCL e DV, respectivamente. Entre os grupos, apenas o grupo DV não mostrou utilidade significativa no uso do escore total do MoCA para diferenciá-lo. Para comparar os subescores do MoCA, os pacientes com DA tiveram pontuações mais altas em amplitude de dígitos, fluência verbal e abstração, mas menor pontuação de recordação tardia em comparação com pacientes com DFT. Conclusão: A pontuação total do MoCA e seus subescores não conseguiram diferenciar pessoas com diferentes tipos de demência no contexto da triagem.

Identification of metabolic pathways and key genes associated with atypical parkinsonism using a systems biology approach.

Atypical parkinsonism (AP) is a group of complex neurodegenerative disorders with marked clinical and pathophysiological heterogeneity. The use of systems biology tools may contribute to the characterization of hub-bottleneck genes, and the identification of its biological pathways to broaden the understanding of the bases of these disorders. A systematic search was performed on the DisGeNET database, which integrates data from expert curated repositories, GWAS catalogues, animal models and the scientific literature. The tools STRING 11.0 and Cytoscape 3.8.2 were used for analysis of protein-protein interaction (PPI) network. The PPI network topography analyses were performed using the CytoHubba 0.1 plugin for Cytoscape. The hub and bottleneck genes were inserted into 4 different sets on the InteractiveVenn. Additional functional enrichment analyses were performed to identify Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and gene ontology for a described set of genes. The systematic search in the DisGeNET database identified 485 genes involved with Atypical Parkinsonism. Superimposing these genes, we detected a total of 31 hub-bottleneck genes. Moreover, our functional enrichment analyses demonstrated the involvement of these hub-bottleneck genes in 3 major KEGG pathways. We identified 31 highly interconnected hub-bottleneck genes through a systems biology approach, which may play a key role in the pathogenesis of atypical parkinsonism. The functional enrichment analyses showed that these genes are involved in several biological processes and pathways, such as the glial cell development, glial cell activation and cognition, pathways were related to Alzheimer disease and Parkinson disease. As a hypothesis, we highlight as possible key genes for AP the MAPT (microtubule associated protein tau), APOE (apolipoprotein E), SNCA (synuclein alpha) and APP (amyloid beta precursor protein) genes.

Differential associations of clinical features with cerebrospinal fluid biomarkers in dementia with Lewy bodies and Alzheimer's disease.

AIM: To explore associations of cerebrospinal fluid biomarkers of neurodegeneration and amyloidosis with caregiver burden, cognition and functionality in dementia with Lewy bodies (DLB) paired with late-onset Alzheimer's disease (AD) and healthy older people. METHODS: Consecutive outpatients with DLB were matched with outpatients with AD according to sex, cognitive scores and dementia stage, and with cognitively healthy controls according to age and sex to investigate associations of cerebrospinal fluid amyloid-ß (Aß42,Aß40,Aß38), tau, phospho-tau Thr181, ubiquitin, α-synuclein and neurofilament light with caregiver burden, functionality, reverse digit span, a clock drawing test, Mini-Mental State Examination (MMSE) and Severe MMSE, adjusted for sex, age, education, dementia duration and APOE-ε4 alleles. RESULTS: Overall, 27 patients with DLB (78.98 ± 9.0 years-old; eleven APOE-ε4 +) were paired with 27 patients with AD (81.50 ± 5.8 years-old; twelve APOE-ε4 +) and 27 controls (78.98 ± 8.7 years-old; four APOE-ε4 +); two-thirds were women. In AD, Aß42/Aß38 and Aß42 were lower, while tau/Aß42 and phospho-tau Thr181/Aß42 were higher; α-synuclein/Aß42 was lower in DLB and higher in AD. The following corrected associations remained significant: in DLB, instrumental functionality was inversely associated with tau/phospho-tau Thr181 and tau/Aß42, and reverse digit span associated with α-synuclein; in AD, instrumental functionality was inversely associated with neurofilament light, clock drawing test scores inversely associated with phospho-tau Thr181/Aß42 and α-synuclein/Aß42, and Severe MMSE inversely associated with tau/Aß42 and tau/phospho-tau Thr181. CONCLUSIONS: Cerebrospinal fluid phospho-tau Thr181 in DLB was similar to AD, but not Aß42. In associations with test scores, biomarker ratios were superior to isolated biomarkers, while worse functionality was associated with axonal degeneration only in AD.

Cambios en la marcha asociados con demencia por cuerpos de Lewy: una revisión narrativa de la literatura / Gait changes associated with Lewy body dementia: a narrative review of the literature

RESUMEN INTRODUCCIÓN: La demencia por cuerpos de Lewy (DCL) es una enfermedad neurodegenerativa con alta prevalencia y a menudo subdiagnosticada. En las demencias pueden presentarse alteraciones en la marcha que potencialmente permitan identificar su subtipo y dar una orientación clínica, diagnóstica y terapéutica temprana. Esta revisión narrativa de la literatura busca revisar los cambios de la marcha que se han descrito asociados con DCL. MATERIALES Y MÉTODOS: Se realizó una revisión de la literatura sobre la relación de las alteraciones de la marcha con la DCL. Se seleccionaron los siguientes parámetros de búsqueda mediante el buscador Scopus: ((falls and dementia and gait and (evaluation or analysis))). Los datos se ordenaron según relevancia y se obtuvieron 267 resultados. Igualmente, se hizo una búsqueda en PubMed, para a la que se introdujeron los términos (gait and lewy-body-disease), y no se utilizaron otros filtros; se obtuvieron 139 resultados. Se hizo una selección no sistemática de los artículos para llevar a cabo una revisión narrativa acerca de los cambios en la marcha asociados con DCL. RESULTADOS: Las alteraciones en la marcha pueden tener un valor predictor importante en la DCL. Los pacientes con demencias no debido a EA o causas vasculares muestran un deterioro de la funcionalidad física más rápido comparado con pacientes con EA y sin problemas cognitivos. La priorización incorrecta de las tareas, evidenciada en la EP, también es observable en los pacientes con DCL, y se asocia con el paradigma de doble tarea en el paciente con trastorno neurocognitivo mayor. El congelamiento de la marcha, también conocido como bloqueo de la marcha, se ha asociado con mayor progresión de la alteración cognitiva. Los pacientes con DCL también presentan un mayor compromiso en el tiempo de balanceo y la variabilidad de duración de la zancada, como también peor desempeño en ritmo y variabilidad de la marcha, e inestabilidad de la marcha, con posturas inadecuadas. CONCLUSIONES: Existe una relación entre la DCL y las caídas en el adulto mayor. En este grupo de edad, los cambios en la marcha y en las pruebas de desempeño podrían tener una utilidad clínica como factores asociados a con DCL, así como con las caídas. Al parecer, existe una variación característica entre los parámetros de la marcha y los subtipos de demencias que puede tener un valor como marcador diagnóstico. Se requieren más estudios con respecto a este tema puesto que hay escasa evidencia disponible hasta el momento, lo cual impide definir con mayor precisión las alteraciones más sensibles de cada dominio de la marcha que permitan diferenciar el envejecimiento normal del patológico.

ABSTRACT INTRODUCTION: Lewy body dementia is a highly prevalent neurodegenerative disease and often goes unnoticed due to little knowledge about it. In dementias there may be gait alterations that potentially allow the identification of its subtype and provide early clinical, diagnostic, and therapeutic guidance. This narrative review of the literature aims to review gait changes that have been described as associated with Lewy body dementia. MATERIALS AND METHODS: A literature review was carried out on the relationship of gait disturbances and LBD. The following search parameters were selected using the Scopus search engine: ((falls and dementia and gait and (evaluation or analysis))). The data were ordered according to relevance, obtaining 267 results. Likewise, a search was made in PubMed, using the terms (gait and lewy-body-disease), and no other filters were used, obtaining 139 results. A non-systematic selection of literature was made to carry out a narrative review about the changes in gait associated with LBD. RESULTS: We found that gait disturbances may have an important predictive value in LBD. Patients with dementias not due to AD or vascular causes have a faster deterioration of physical function compared to patients with AD and without cognitive problems. The incorrect prioritization of tasks evidenced in PD is also observable in patients with LBD and is associated with the "dual-task" paradigm in patients with major neurocognitive disorder. Freezing of gait, also known as motor block or "freezing of gait" has been associated with a greater progression of cognitive impairment. Patients with LBD also show greater compromise in swing time, stride duration variability, poorer performance in gait pace and variability, and gait instability with inappropriate postures. CONCLUSIONS: We observe that there is a relationship between LBD and falls in the elderly. Changes in gait and performance tests could have clinical utility as factors associated with LBD as well as falls in the elderly. There appears to be a characteristic variation between gait parameters and dementia subtypes that may have value as a diagnostic marker. More studies are required on this subject since there is little evidence available to date, which makes it impossible to define with greater precision the most sensitive alterations in each domain of gait that make it possible to differentiate normal from pathological aging.

Classification of Patients with Alzheimer's Disease and Dementia with Lewy Bodies using Resting EEG Selected Features at Sensor and Source Levels: A Proof-of-Concept Study.

BACKGROUND: Early differentiation between Alzheimer's disease (AD) and Dementia with Lewy Bodies (DLB) is important for accurate prognosis, as DLB patients typically show faster disease progression. Cortical neural networks, necessary for human cognitive function, may be disrupted differently in DLB and AD patients, allowing diagnostic differentiation between AD and DLB. OBJECTIVE: This proof-of-concept study assessed whether the application of machine learning techniques to data derived from resting-state electroencephalographic (rsEEG) rhythms (discriminant sensor power, 19 electrodes) and source connectivity (between five cortical regions of interest) allowed differentiation between DLB and AD. METHODS: Clinical, demographic, and rsEEG datasets from DLB patients (N=30), AD patients (N=30), and control seniors (NOld, N=30), matched for age, sex, and education, were taken from our international database. Individual (delta, theta, alpha) and fixed (beta) rsEEG frequency bands were included. The rsEEG features for the classification task were computed at both sensor and source levels. The source level was based on eLORETA freeware toolboxes for estimating cortical source activity and linear lagged connectivity. Fluctuations of rsEEG recordings (band-pass waveform envelopes of each EEG rhythm) were also computed at both sensor and source levels. After blind feature reduction, rsEEG features served as input to support vector machine (SVM) classifiers. Discrimination of individuals from the three groups was measured with standard performance metrics (accuracy, sensitivity, and specificity). RESULTS: The trained SVM two-class classifiers showed classification accuracies of 97.6% for NOld vs. AD, 99.7% for NOld vs. DLB, and 97.8% for AD vs. DLB. Three-class classifiers (AD vs. DLB vs. NOld) showed classification accuracy of 94.79%. CONCLUSION: These promising preliminary results should encourage future prospective and longitudinal cross-validation studies using higher resolution EEG techniques and harmonized clinical procedures to enable the clinical application of these machine learning techniques.

Cerebrospinal Fluid Neurotransmitters, Cytokines, and Chemokines in Alzheimer's and Lewy Body Diseases.

BACKGROUND: Alzheimer's disease (AD) and Lewy body disease (LBD) are complex neurodegenerative disorders that have been associated with brain inflammation and impaired neurotransmission. OBJECTIVE: We aimed to determine concentrations of multiple cytokines, chemokines, and neurotransmitters previously associated with brain inflammation and synapse function in cerebrospinal fluid (CSF) from AD and LBD patients. METHODS: We examined a panel of 50 analytes comprising neurotransmitters, cytokines, chemokines, and hormones in CSF in a cohort of patients diagnosed with mild cognitive impairment (MCI), AD, LBD, or non-demented controls (NDC). RESULTS: Among neurotransmitters, noradrenaline (NA) was increased in AD CSF, while homovanillic acid (HVA), a dopamine metabolite, was reduced in both AD and LBD CSF relative to NDC. Six cytokines/chemokines out of 30 investigated were reliably detected in CSF. CSF vascular endothelial growth factor (VEGF) was significantly reduced in LBD patients relative to NDC. CONCLUSIONS: CSF alterations in NA, HVA, and VEGF in AD and LBD may reflect pathogenic features of these disorders and provide tools for improved diagnosis. Future studies are warranted to replicate current findings in larger, multicenter cohorts.

Associations of Neuropsychiatric Features with Cerebrospinal Fluid Biomarkers of Amyloidogenesis and Neurodegeneration in Dementia with Lewy Bodies Compared with Alzheimer's Disease and Cognitively Healthy People.

BACKGROUND: Behavioral features may reflect proteinopathies predicting pathophysiology in neurodegenerative diseases. OBJECTIVE: We aimed to investigate associations of cerebrospinal fluid biomarkers of amyloidogenesis and neurodegeneration with neuropsychiatric features in dementia with Lewy bodies (DLB) compared with late-onset Alzheimer's disease (AD) and cognitively healthy people. METHODS: Consecutive outpatients with DLB were paired with outpatients with AD according to sex, dementia stage, and cognitive scores, and with cognitively healthy controls according to sex and age to investigate associations of cerebrospinal fluid amyloid-ß (Aß)42, Aß40, Aß38, total tau, phospho-tau Thr181, α-synuclein, ubiquitin, and neurofilament light with neuropsychiatric features according to APOEɛ4 carrier status. RESULTS: Overall, 27 patients with DLB (78.48±9.0 years old, eleven APOEɛ4 carriers) were paired with 27 patients with AD (81.00±5.8 years old, twelve APOEɛ4 carriers) and 27 controls (78.48±8.7 years old, four APOEɛ4 carriers); two thirds were women. Behavioral burden was more intense in DLB. Biomarker ratios reflecting amyloidogenesis and neurodegeneration in DLB were more similar to those in AD when patients carried APOEɛ4 alleles. After corrections for false discovery rates, the following associations remained significant: in DLB, dysphoria was associated with tauopathy and indirect measures of amyloidogenesis, while in AD, agitation, and night-time behavior disturbances were associated with tauopathy, and delusions were associated with tauopathy and indirect measures of amyloidogenesis. CONCLUSION: Biomarker ratios were superior to Aß and tau biomarkers predicting neuropsychiatric symptoms when associations with isolated biomarkers were not significant. At the end, APOEɛ4 carrier status influenced amyloidogenesis and tau pathology in DLB and in AD, and axonal degeneration only in DLB.

Anosognosia in dementia with Lewy bodies: a systematic review / Anosognosia na demência com corpos de Lewy: uma revisão sistemática

ABSTRACT Background: Anosognosia, i.e. lack of awareness of one's own symptoms, is a very common finding in patients with dementia and is related to neuropsychiatric symptoms and worse prognosis. Although dementia with Lewy bodies (DLB) is the second most common form of degenerative dementia, literature on anosognosia in this disease is scarce. Objectives: This paper aimed to review the current evidence on anosognosia in patients with DLB, including its prevalence in comparison with other neurological conditions, its severity and anatomical correlations. Methods: Database searches were performed in PubMed, Web of Knowledge and PsycINFO for articles assessing anosognosia in DLB. A total of 243 studies were retrieved, but only six were included in the review. Results: Potential risk of selection, comparison or outcome biases were detected in relation to all the studies selected. Most of the studies used self-report memory questionnaires to assess cognitive complaints and compared their results to scores from informant-based instruments or to participants' cognitive performance in neuropsychological tasks. Subjects with DLB had worse awareness regarding memory than healthy older controls, but the results concerning differences in anosognosia between DLB and Alzheimer's disease (AD) patients were inconsistent across studies. Presence of AD pathology and neuroimaging biomarkers appeared to increase the prevalence of anosognosia in individuals with DLB. Conclusion: Anosognosia is a common manifestation of DLB, but it is not clear how its prevalence and severity compare with AD. Co-existence of AD pathology seems to play a role in memory deficit awareness in DLB.

RESUMO Introdução: Anosognosia, i.e. a perda da consciência dos próprios sintomas, é um achado muito comum em pacientes com demência e está relacionada a sintomas neuropsiquiátricos e a pior prognóstico. Embora a doença por Corpos de Lewy (DCL) seja a segunda demência degenerativa mais comum, há pouca evidência sobre anosognosia nessa doença. Objetivos: Este artigo teve como objetivo revisar a evidência disponível sobre anosognosia em pacientes com DCL, incluindo sua prevalência em comparação a outras condições neurológicas, gravidade e correlações anatômicas. Métodos: Foram feitas buscas nos bancos de dados PubMed, Web of Knowledge e PsycINFO por artigos que avaliassem anosognosia na DCL. Um total de 243 estudos foi encontrado, mas apenas 6 foram incluídos nesta revisão. Resultados: Potenciais riscos de viés de seleção, comparação ou resultado foram encontrados em todos os estudos selecionados. A maior parte dos estudos utilizou questionários de memória preenchidos pelo próprio paciente e os comparou a resultados de instrumentos preenchidos por informantes ou à performance cognitiva em tarefas neuropsicológicas. Indivíduos com DCL têm pior consciencia de memória do que idosos saudáveis, mas os resultados tocantes à diferença de anosognosia entre DCL e doença de Alzheimer (DA) são inconsistentes entre estudos. A presença de achados patológicos e de neuroimagem de DA parece aumentar a prevalência de anosognosia entre pacientes com DCL. Conclusão: Anosognosia é uma manifestação comum da DCL, mas não é possível afirmar como sua prevalência e gravidade se comparam à DA. A coexistência de achados patológicos de DA parece influenciar a consciência de déficits de memória na DCL.

Anosognosia for memory in dementia with Lewy bodies compared with Alzheimer's disease.

OBJECTIVES: Anosognosia is the inability to recognize one's own symptoms. Although dementia with Lewy bodies (DLB) is the second most common degenerative dementia, there is little evidence of memory deficit awareness in this condition. The objectives of this research were to compare anosognosia between individuals with DLB and dementia due to Alzheimer's disease (AD) and to evaluate whether medial temporal atrophy, a marker of AD pathology, could help to explain different rates of anosognosia in DLB and dementia due to AD. METHODS/DESIGN: This is a cross-sectional study that took place at the Memory Clinic of D'Or Institute for Research and Education (IDOR). Twenty individuals with DLB and 20 with dementia due to AD were included in this study. We assessed anosognosia for memory using an index derived from subjective memory complaints (using the Memory Complaint Questionnaire) and from the performance in memory neuropsychological testing (Rey Auditory Verbal Learning Test). Thirty-one participants also underwent brain Magnetic Resonance Imaging to evaluate hippocampal atrophy with a visual scale (MTA-score [medial temporal atrophy score]). RESULTS: There was no significant difference between groups regarding age, years of education, sex or time of disease. Individuals with DLB had a higher index of anosognosia than dementia due to AD (2.92 and 1.87; p = 0.024), meaning worse awareness of memory deficits. MTA-score was slightly higher in dementia due to AD than in DLB, albeit without statistical significance. CONCLUSION: Our study was the first to demonstrate that anosognosia for memory is worse in DLB than in dementia due to AD. This finding supports the hypothesis that anosognosia in DLB is a heterogeneous phenomenon.

Prolyl Endopeptidase-Like Facilitates the α-Synuclein Aggregation Seeding, and This Effect Is Reverted by Serine Peptidase Inhibitor PMSF.

The aggregation of α-synuclein (α-Syn) is a characteristic of Parkinson's disease (PD). α-Syn oligomerization/aggregation is accelerated by the serine peptidase, prolyl oligopeptidase (POP). Factors that affect POP conformation, including most of its inhibitors and an impairing mutation in its active site, influence the acceleration of α-Syn aggregation resulting from the interaction of these proteins. It is noteworthy, however, that α-Syn is not cleaved by POP. Prolyl endopeptidase-like (PREPL) protein is structurally related to the serine peptidases belonging to the POP family. Based on the α-Syn-POP studies and knowing that PREPL may contribute to the regulation of synaptic vesicle exocytosis, when this protein can encounter α-Syn, we investigated the α-Syn-PREPL interaction. The binding of these two human proteins was observed with an apparent affinity constant of about 5.7 µM and, as in the α-Syn assays with POP, the presence of PREPL accelerated the oligomerization/aggregation events, with no α-Syn cleavage. Furthermore, despite this lack of hydrolytic cleavage, the serine peptidase active site inhibitor phenylmethylsulfonyl fluoride (PMSF) abolished the enhancement of the α-Syn aggregation by PREPL. Therefore, given the attention to POP inhibitors as potential drugs to treat synucleinopathies, the present data point to PREPL as another potential target to be explored for this purpose.

Correlates of neuropsychiatric and motor tests with language assessment in patients with Lewy body dementia

Abstract Background Lewy body dementia (LBD) impairs performance in daily activities and affects motor, language and visuospatial tasks. Objective We aimed to correlate neuropsychiatric and motor assessments with language and visual organization tests in LBD. Methods Twenty-two patients with dementia with Lewy bodies and ten patients with Parkinson's disease dementia participated on a cross-sectional study that assessed cognition, functionality, caregiver burden, verbal fluency, the primer-level dictation section of the Boston Diagnostic Aphasia Examination (PLD-BDAE), the Hooper Visual Organization Test, the Neuropsychiatric Inventory and the Movement Disorder Society - Unified Parkinson's Disease Rating Scale. Results Language and visuospatial test results followed motor impairment and general cognitive performance. Whereas visual organization did not predict performance in the PLD-BDAE, visuospatial abilities and verbal fluency were concurrently associated, suggesting that linguistic impairment in LBD may be attributed to neuropsychological components of cognition and language. Only visual organization was associated with behaviour, suggesting that neuropsychiatric symptoms associate with differential impairment of visual organization in comparison with language in LBD. Schooling did not affect visual organization or language test performance, while the length of dementia was negatively associated with visual organization and verbal fluency. Discussion Though visual organization tests follow behaviour and motor performance in LBD, there is differential impairment regarding language skills.

Unilateral intranigral administration of ß-sitosterol ß-D-glucoside triggers pathological α-synuclein spreading and bilateral nigrostriatal dopaminergic neurodegeneration in the rat.

The spreading and accumulation of α-synuclein and dopaminergic neurodegeneration, two hallmarks of Parkinson's disease (PD), have been faithfully reproduced in rodent brains by chronic, oral administration of ß-sitosterol ß-D-glucoside (BSSG). We investigated whether a single injection of BSSG (6 µg BSSG/µL DMSO) in the left substantia nigra of Wistar rats causes the same effects. Mock DMSO injections and untreated rats formed control groups. We performed immunostainings against the pathological α-synuclein, the dopaminergic marker tyrosine hydroxylase (TH), the neuroskeleton marker ß-III tubulin, the neurotensin receptor type 1 (NTSR1) as non-dopaminergic phenotype marker and Fluro-Jade C (F-J C) label for neurodegeneration. Using ß-galactosidase (ß-Gal) assay and active caspase-3 immunostaining, we assessed cell death mechanisms. Golgi-Cox staining was used to measure the density and types of dendritic spines of striatal medium spiny neurons. Motor and non-motor alterations were also evaluated. The study period comprised 15 to 120 days after the lesion. In the injured substantia nigra, BSSG caused a progressive α-synuclein aggregation and dopaminergic neurodegeneration caused by senescence and apoptosis. The α-synuclein immunoreactivity was also present within microglia cells. Decreased density of dopaminergic fibers and dendritic spines also occurred in the striatum. Remarkably, all the histopathological changes also appeared on the contralateral nigrostriatal system, and α-synuclein aggregates were present in other brain regions. Motor and non-motor behavioral alterations were progressive. Our data show that the stereotaxic BSSG administration reproduces PD α-synucleinopathy phenotype in the rat. This approach will aid in identifying the spread mechanism of α-synuclein pathology and validate anti-synucleinopathy therapies.

Ekbom Syndrome associated with Lewy Body Dementia: A case report.

Ekbom Syndrome, also known as parasitosis delusion or psychogenic parasitosis, is a rare condition in which patients present with a fixed belief of being infested by parasites, vermin or small insects, along with tactile hallucinations (such as pruritus or sensations of the parasites crawling over or under the skin). The syndrome may occur idiopathically or be associated with other medical conditions and drug use. This case report describes the occurrence of Ekbom syndrome in a patient diagnosed with Lewy Body Dementia (LBD), a neurodegenerative disease that commonly presents with sensory perception and thought disorders and other neuropsychiatric symptoms. Although visual hallucination is considered a core diagnostic criterion, other modalities of psychiatric symptoms can also occur posing a further challenge for correct diagnosis. Proper recognition allows early diagnosis and adequate treatment, preventing hazardous antipsychotic use in these patients.

A síndrome de Ekbom, também conhecida como delírio parasitário ou parasitose psicogênica, é uma condição rara na qual os pacientes apresentam crença fixa de estarem infestados por parasitas, vermes ou insetos, acompanhada de alucinações táteis (como prurido ou sensação dos parasitas andando sobre ou sob a pele). A síndrome pode ocorrer de forma idiopática ou associada a outras condições médicas ou uso de drogas. Este relato de caso descreve a ocorrência da síndrome de Ekbom em um paciente diagnosticado com Demência com corpos de Lewy (DCL), uma doença degenerativa que comumente se apresenta com desordens de sensopercepção e pensamento, e outros sintomas neuropsiquiátricos. A alucinação visual é considerada um dos critérios diagnósticos nucleares, entretanto outras modalidades de sintomas psiquiátricos podem ocorrer criando desafios adicionais ao diagnóstico correto. O reconhecimento apropriado permite o diagnóstico precoce e tratamento adequado, prevenindo o uso arriscado de antipsicóticos nesses pacientes.

Ekbom Syndrome associated with Lewy Body Dementia: A case report / Síndrome de ekbom associada à demência com corpos de lewy: um relato de caso

ABSTRACT Ekbom Syndrome, also known as parasitosis delusion or psychogenic parasitosis, is a rare condition in which patients present with a fixed belief of being infested by parasites, vermin or small insects, along with tactile hallucinations (such as pruritus or sensations of the parasites crawling over or under the skin). The syndrome may occur idiopathically or be associated with other medical conditions and drug use. This case report describes the occurrence of Ekbom syndrome in a patient diagnosed with Lewy Body Dementia (LBD), a neurodegenerative disease that commonly presents with sensory perception and thought disorders and other neuropsychiatric symptoms. Although visual hallucination is considered a core diagnostic criterion, other modalities of psychiatric symptoms can also occur posing a further challenge for correct diagnosis. Proper recognition allows early diagnosis and adequate treatment, preventing hazardous antipsychotic use in these patients.

RESUMO A síndrome de Ekbom, também conhecida como delírio parasitário ou parasitose psicogênica, é uma condição rara na qual os pacientes apresentam crença fixa de estarem infestados por parasitas, vermes ou insetos, acompanhada de alucinações táteis (como prurido ou sensação dos parasitas andando sobre ou sob a pele). A síndrome pode ocorrer de forma idiopática ou associada a outras condições médicas ou uso de drogas. Este relato de caso descreve a ocorrência da síndrome de Ekbom em um paciente diagnosticado com Demência com corpos de Lewy (DCL), uma doença degenerativa que comumente se apresenta com desordens de sensopercepção e pensamento, e outros sintomas neuropsiquiátricos. A alucinação visual é considerada um dos critérios diagnósticos nucleares, entretanto outras modalidades de sintomas psiquiátricos podem ocorrer criando desafios adicionais ao diagnóstico correto. O reconhecimento apropriado permite o diagnóstico precoce e tratamento adequado, prevenindo o uso arriscado de antipsicóticos nesses pacientes.

The center of olfactory bulb-seeded α-synucleinopathy is the limbic system and the ensuing pathology is higher in male than in female mice.

At early disease stages, Lewy body disorders are characterized by limbic vs. brainstem α-synucleinopathy, but most preclinical studies have focused solely on the nigrostriatal pathway. Furthermore, male gender and advanced age are two major risk factors for this family of conditions, but their influence on the topographical extents of α-synucleinopathy and the degree of cell loss are uncertain. To fill these gaps, we infused α-synuclein fibrils in the olfactory bulb/anterior olfactory nucleus complex-one of the earliest and most frequently affected brain regions in Lewy body disorders-in 3-month-old female and male mice and in 11-month-old male mice. After 6 months, we observed that α-synucleinopathy did not expand significantly beyond the limbic connectome in the 9-month-old male and female mice or in the 17-month-old male mice. However, the 9-month-old male mice had developed greater α-synucleinopathy, smell impairment and cell loss than age-matched females. By 10.5 months post-infusion, fibril treatment hastened mortality in the 21.5-month-old males, but the inclusions remained centered in the limbic system in the survivors. Although fibril infusions reduced the number of cells expressing tyrosine hydroxylase in the substantia nigra of young males at 6 months post-infusion, this was not attributable to true cell death. Furthermore, mesencephalic α-synucleinopathy, if present, was centered in mesolimbic circuits (ventral tegmental area/accumbens) rather than within strict boundaries of the nigral pars compacta, which were defined here by tyrosine hydroxylase immunolabel. Nonprimate models cannot be expected to faithfully recapitulate human Lewy body disorders, but our murine model seems reasonably suited to (i) capture some aspects of Stage IIb of Lewy body disorders, which displays a heavier limbic than brainstem component compared to incipient Parkinson's disease; and (ii) leverage sex differences and the acceleration of mortality following induction of olfactory α-synucleinopathy.

miR-7 Replacement Therapy in Parkinson's Disease.

The present review examines whether the microRNA 7 (miR-7) holds potential for slowing Parkinson's disease (PD) progression. First, the accurate expression of miR-7 allows for normal development, physiology, and neurogenesis in the central nervous system, also keeping alpha-synuclein (α-Syn) at the physiological level. Second, patients with PD and parkinsonian MPTP-induced animals exhibit a significant decrease of miR-7 in brain areas associated with dopaminergic neurodegeneration. Depletion of miR-7 in the substantia nigra of clinical samples is related to α-Syn accumulation, loss of dopaminergic cells, and reduction of dopamine in the striatum. Therefore, the goal of a miR-7- replacement therapy is to downregulate α-Syn and other PD-related genes, achieving multi-target benefits regarding oxidative stress, mitochondrial health, cell glycolysis, apoptosis, and inhibition of inflammasome activation. While a disease-modifying drug is a major unmet need for the clinical management of PD, an miR-7-replacement therapy presents a striking potential against critical mechanisms of neuropathology. Such innovative treatment would reduce α-Syn accumulation in the Lewy bodies and preserve remaining neurons yet viable at the time of diagnosis, thus slowing disease progression from the early phase of PD characterized by a relatively mild motor impairment to an advanced and more disabling stage.

Risk of Conversion to Dementia in a Mild Behavioral Impairment Group Compared to a Psychiatric Group and to a Mild Cognitive Impairment Group.

BACKGROUND: There is insufficient available information on behavioral changes in the absence of cognitive impairment as factors increasing the risk of conversion to dementia. OBJECTIVE: To observe and analyze patients with mild behavioral impairment (MBI), mild cognitive impairment (MCI), and a psychiatry group (PG) to compare the risk of progression to dementia. METHODS: From 677 initially assessed ≥60-year-old patients, a series of 348 patients was studied for a five-year period until censoring or conversion to dementia: 96 with MBI, 87 with MCI, and 165 with general psychiatry disorders, including 4 subgroups: Anxiety, Depression, Psychosis and Others. All patients were assessed with clinical, psychiatric, neurological, neuropsychological, and neuroimaging studies. RESULTS: From 348 patients, 126 evolved to dementia (36.2%). Conversion was significantly higher in MBI (71.5%), followed by the MCI-MBI overlap (59.6%) and MCI (37.8%) groups, compared to PG (13.9%) (Log-rank p < 0.001). MCI patients mostly converted to Alzheimer's dementia, while MBI converted to frontotemporal dementia and Lewy body dementia. Patients in PG converted to Lewy body dementia and frontotemporal dementia. CONCLUSION: Conversion to dementia is significantly higher in patients with neuropsychiatric symptoms. The MBI concept generates a new milestone in the refining of diagnosis of neurodegenerative diseases and the possibility of creating neuropsychiatric profiles. Its earlier identification will allow new possibilities for therapeutic intervention.

ALBA Screening Instrument (ASI): A brief screening tool for Lewy Body Dementia.

BACKGROUND: Early detection of neurodegenerative diseases is essential for treatment and proper care of these patients. Screening tools available today are effective for several types of dementia. However, there is no one specific for Lewy Body Dementia (LBD). OBJECTIVES: The aim of this paper is to present a tool for early detection of LBD, accessible even for non-medical staff. METHODS: We stratified subjects (MMSE>20) into four groups: health controls (HC), Mild Cognitive Impairment (MCI), LBD and other dementias (Alzheimer and vascular). All subjects (age range 50-90) were examined with a comprehensive neuropsychological and neuropsychiatric evaluation, as well as neuroimaging to differentiate diagnosis between groups, fulfilling corresponding criteria. Both neurologists and neuropsychologists were blind to the performance on clinical evaluations and ASI, respectively. The sensitivity and specificity of the instrument were determined to differentiate LBD from other groups. RESULTS: We evaluated 427 subjects, 91 HC, 140 with MCI and 196 with dementia. In the dementia group, 75 were diagnosed with LBD and 121 with other dementias. ASI total score was 12.7±0.4 for LBD, 2.9±0.2 for HC, 5±0.7 for MCI, and 5.4±2.6 for other causes of dementia. ROC curve analysis showed a sensitivity of 90.7% and a specificity of 93.6% stands, with 9 as the cutoff with better test performance compared against other groups. CONCLUSION: ASI is a brief screening tool for LBD with high sensitivity and specificity and useful even for non-medical staff.

Robin Williams' suicide: a case study / O suicídio de Robin Williams: estudo de caso

Abstract Introduction: The world renowned comedian and four-time Oscar nominated actor Robin Williams died on August 11, 2014. From the outset, the news indicated that his death was believed to be a suicide and this was later confirmed to be true by the autopsy reports. Williams had been suffering from severe depression, which is believed to be the leading contributor to his suicide. In this case study, I will highlight the event of the actor's suicide and the main risk factors along with depression leading to his tragic death. As of the end of 2015, no other case study seemed to have addressed or explored the links between the cause (or causes) and events leading to Robin Williams' suicide. Case description: Robin Williams was suffering from relationship problems, financial problems, drug addiction, and major depression. All of these factors led to his suicide. Comments: The chances of committing suicide drastically increase in the presence of any of the key risk factors. Unfortunately, the actor Robin Williams was dealing with four of the major risk factors all together, which put him at a high risk of committing suicide and eventually led to his tragic death.

Resumo Introdução: O ator Robin Williams, comediante reconhecido internacionalmente e quatro vezes indicado ao Oscar, faleceu no dia 11 de agosto de 2014. Desde o início, os noticiários indicavam que sua morte provavelmente resultara de suicídio, e isso foi confirmado posteriormente nos relatórios da autópsia. Williams vinha sofrendo de depressão severa, a qual, acredita-se, foi o fator que mais contribuiu para seu suicídio. Neste estudo de caso, vou discorrer sobre o suicídio do ator e sobre os principais fatores de risco, além da depressão, que levaram à sua morte trágica. Do final de 2015 para cá, nenhum outro estudo de caso parece ter abordado ou explorado as associações entre a causa (ou as causas) e os eventos que levaram ao suicídio do ator Robin Williams. Descrição do caso: Robin Williams vinha sofrendo com problemas de relacionamento, problemas financeiros, abuso de drogas e depressão severa. Todos esses fatores levaram ao seu suicídio. Comentários: As chances de cometer suicídio aumentam drasticamente na presença de qualquer fator de risco chaves. Infelizmente, o ator Robin Williams estava exposto a quatro fatores de risco chaves simultaneamente, colocando-o sob um alto risco de cometer suicídio, o que eventualmente culminou com sua trágica morte.