Mapping brain morphology to cognitive deficits: a study on PD-CRS scores in Parkinson's disease with mild cognitive impairment.

Background: The Parkinson's Disease-Cognitive Rating Scale (PD-CRS) is a widely used tool for detecting mild cognitive impairment (MCI) in Parkinson's Disease (PD) patients, however, the neuroanatomical underpinnings of this test's outcomes require clarification. This study aims to: (a) investigate cortical volume (CVol) and cortical thickness (CTh) disparities between PD patients exhibiting mild cognitive impairment (PD-MCI) and those with preserved cognitive abilities (PD-IC); and (b) identify the structural correlates in magnetic resonance imaging (MRI) of overall PD-CRS performance, including its subtest scores, within a non-demented PD cohort. Materials and methods: This study involved 51 PD patients with Hoehn & Yahr stages I-II, categorized into two groups: PD-IC (n = 36) and PD-MCI (n = 15). Cognitive screening evaluations utilized the PD-CRS and the Montreal Cognitive Assessment (MoCA). PD-MCI classification adhered to the Movement Disorder Society Task Force criteria, incorporating extensive neuropsychological assessments. The interrelation between brain morphology and cognitive performance was determined using FreeSurfer. Results: Vertex-wise analysis of the entire brain demonstrated a notable reduction in CVol within a 2,934 mm2 cluster, encompassing parietal and temporal regions, in the PD-MCI group relative to the PD-IC group. Lower PD-CRS total scores correlated with decreased CVol in the middle frontal, superior temporal, inferior parietal, and cingulate cortices. The PD-CRS subtests for Sustained Attention and Clock Drawing were associated with cortical thinning in distinct regions: the Clock Drawing subtest correlated with changes in the parietal lobe, insula, and superior temporal cortex morphology; while the PD-CRS frontal-subcortical scores presented positive correlations with CTh in the transverse temporal, medial orbitofrontal, superior temporal, precuneus, fusiform, and supramarginal regions. Additionally, PD-CRS subtests for Semantic and Alternating verbal fluency were linked to CTh changes in orbitofrontal, temporal, fusiform, insula, and precentral regions. Conclusion: PD-CRS performance mirrors neuroanatomical changes across extensive fronto-temporo-parietal areas, covering both lateral and medial cortical surfaces, in PD patients without dementia. The observed changes in CVol and CTh associated with this cognitive screening tool suggest their potential as surrogate markers for cognitive decline in PD. These findings warrant further exploration and validation in multicenter studies involving independent patient cohorts.

Development and validation of the MultiScent-20 digital odour identification test using item response theory.

Although validated and reliable psychophysical tests of olfactory function are available, an easy-to-use and feasible test has yet to be developed. This study aimed to design a digital odour identification test, evaluate its validity, assess its reliability, establish a normative curve, and explore the impact of demographic factors. The odour identification test was presented with the Multiscent-20, a hand-held, tablet-like digital scent device that features an integrated odour digital delivery system. The identification performance on the 20 odours was assessed using item response theory (IRT). The normative curve was established by administering the test to a large sample of participants (n = 1299). The mean identification score was 17.5 (SD = 2.1). The two-parameter logistic IRT model provided the best fit, revealing variation in item discrimination and difficulty parameters. Educational attainment influenced performance, with primary education associated with lower scores. Additionally, sex was not found to be associated with performance. This study provides initial evidence supporting the validity and reliability of use of the Multiscent-20 as a digital odour identification test. The test's automation and portability enable the standardized delivery of olfactory stimuli and efficient automatic recording and scoring of responses.

Differential diagnosis between multiple sclerosis and leukodystrophies - A scoping review.

Multiple Sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS) characterized by damage to the myelin sheaths of oligodendrocytes. Currently, there is no specific biomarker to identify the disease; however, a diagnostic criterion has been established based on patient's clinical, laboratory, and imaging characteristics, which assists in identifying this condition. The primary method for diagnosing MS is the McDonald criteria, first described in 2001 and revised in the years 2005, 2012, and 2017. These criteria have been continuously reviewed to enhance specificity and sensitivity in the diagnosis of MS, thereby reducing errors in its differential diagnosis. An important differential diagnosis that shares overlapping features with MS, mainly the progressive forms, are leukodystrophies with demyelination as underlying pathology. Leukodystrophies comprise a rare group of genetically determined disorders that lead to either demyelination or hypomyelination of the central nervous system that can result neuroimaging changes as well as clinical findings similar to those observed in MS. Thus, systematic evaluation encompassing clinical presentation, neuroimaging findings, and laboratory metrics proves indispensable for a differential diagnosis. As such, this study aimed to establish, clearly and objectively, the similarities and differences between MS and the main demyelinating leukodystrophies. The study analyzed the parameters of the McDonald criteria, including clinical, laboratory, and magnetic resonance imaging aspects, as found in patients with leukodystrophies through scoping literature review. The data were compared with the determinations of the revised 2017 McDonald criteria to facilitate the differential diagnosis of these diseases in clinical practice.

Sleep and memory complaints in long COVID: an insight into clustered psychological phenotypes.

This study evaluated clinical features of individuals with long COVID (5-8 months after diagnosis) who reported sleep and memory problems (62 cases) compared to those without (52 controls). Both groups had a similar mean age (41 vs. 39 years). Around 86% of the participants were non-hospitalized at the time of infection, and none of them were vaccinated at that point. Subsequently, both cases and controls received the vaccine; however, the vaccination rates differed significantly between the groups (30.7% vs. 51.0%). Cases and controls had similar rates of symptoms at acute COVID phase. However, cases were more likely to experience coryza, dyspnea, headache, and nausea/vomiting during long COVID. Regarding new-onset symptoms in long COVID, 12.9% of cases had dyspnea, and 14.5% experienced nausea/vomiting, whereas in the control group there were only 1.9% and 0.0%, respectively. Cases also had a significantly higher prevalence of persistent headache (22.6% vs. 7.7%), and dyspnea (12.9% vs. 0.0). In addition, cases also showed an increased rate of mental health complaints: disability in daily activities (45.2% vs. 9.6%; P < 0.001); concentration/sustained attention difficulties (74.2% vs. 9.6%; P < 0.001); anxiety-Generalized Anxiety Disorder 2-item scale (GAD-2) ≥ 3 (66.1% vs. 34.6%; P = 0.0013); and "post-COVID sadness" (82.3% vs. 40.4%; P < 0.001). We observed a significant correlation between sadness and anxiety in cases, which was not observed in controls (P=0.0212; Spearman correlation test). Furthermore, the frequency of concomitant sadness and anxiety was markedly higher in cases compared to controls (59.7% vs. 19.2%) (P < 0.0001; Mann-Whitney test). These findings highlight a noteworthy association between sadness and anxiety specifically in cases. In conclusion, our data identified concurrent psychological phenotypes in individuals experiencing sleep and memory disturbances during long COVID. This strengthens the existing evidence that SARS-CoV-2 causes widespread brain pathology with interconnected phenotypic clusters. This finding highlights the need for comprehensive medical attention to address these complex issues, as well as major investments in testing strategies capable of preventing the development of long COVID sequelae, such as vaccination.

Floor and ceiling effects on the Montreal Cognitive Assessment in patients with Parkinson's disease in Brazil.

Parkinson's disease (PD) is a common neurodegenerative disease associated with cognitive impairment. The Montreal Cognitive Assessment (MoCA) has been used as a recommended global cognition scale for patients with PD, but there are some concerns about its application, partially due to the floor and ceiling effects. Objective: To explore the floor and ceiling effects on the MoCA in patients with PD in Brazil. Methods: Cross-sectional study with data from patients with PD from five Brazilian Movement Disorders Clinics, excluding individuals with a possible diagnosis of dementia. We analyzed the total score of the MoCA, as well as its seven cognitive domains. The floor and ceiling effects were evaluated for the total MoCA score and domains. Multivariate analyses were performed to detect factors associated with floor and ceiling effects. Results: We evaluated data from 366 patients with PD and approximately 19% of individuals had less than five years of education. For the total MoCA score, there was no floor or ceiling effect. There was a floor effect in the abstraction and delayed memory recall domains in 20% of our sample. The ceiling effect was demonstrated in all domains (80.8% more common in naming and 89% orientation), except delayed recall. Education was the main factor associated with the floor and ceiling effects, independent of region, sex, age at evaluation, and disease duration. Conclusion: The floor and ceiling effects are present in specific domains of the MoCA in Brazil, with a strong impact on education. Further adaptations of the MoCA structure for underrepresented populations may reduce these negative effects.

A doença de Parkinson (DP) é uma doença neurodegenerativa comum associada ao declínio cognitivo. A Avaliação Cognitiva de Montreal (Montreal Cognitive Assessment ­ MoCA) tem sido usada como uma escala de cognição global recomendada para pacientes com DP, mas existem algumas preocupações sobre sua aplicação, em parte pelos efeitos solo e teto. Objetivo: Explorar os efeitos solo e teto na MoCA em pacientes com DP no Brasil. Métodos: Estudo transversal com dados de pacientes com DP oriundos de cinco Clínicas de Distúrbios de Movimento no Brasil, excluindo-se pessoas com possível diagnóstico de demência. Nós analisamos a pontuação total da MoCA, assim como a de seus sete domínios cognitivos. Os efeitos solo e teto foram avaliados para a pontuação total da MoCA e seus domínios. Foram feitas análises multivariadas para a detecção de fatores associados os efeitos solo e teto. Resultados: Nós avaliamos dados de 366 pacientes com DP, e aproximadamente 19% das pessoas tinham menos que cinco anos de escolaridade. Para a pontuação total do MoCA, não houve efeito solo ou teto. Houve efeito solo nos domínios abstração e memória de evocação tardia em 20% de nossa amostra. O efeito teto foi demonstrado em todos os domínios (80,8% mais comum em nomeação e 89% orientação), com exceção de memória de evocação tardia. A educação foi o principal fator associado aos efeitos solo e teto, independentemente de região, sexo, idade na avaliação e duração da doença. Conclusão: Os efeitos solo e teto estão presentes em domínios específicos da MoCA no Brasil, com forte impacto da educação. Adaptações adicionais à estrutura da MoCA para populações vulneráveis podem reduzir esses efeitos negativos.

Altered structural connectivity in olfactory disfunction after mild COVID-19 using probabilistic tractography.

We aimed to investigate changes in olfactory bulb volume and brain network in the white matter (WM) in patients with persistent olfactory disfunction (OD) following COVID-19. A cross-sectional study evaluated 38 participants with OD after mild COVID-19 and 24 controls, including Sniffin' Sticks identification test (SS-16), MoCA, and brain magnetic resonance imaging. Network-Based Statistics (NBS) and graph theoretical analysis were used to explore the WM. The COVID-19 group had reduced olfactory bulb volume compared to controls. In NBS, COVID-19 patients showed increased structural connectivity in a subnetwork comprising parietal brain regions. Regarding global network topological properties, patients exhibited lower global and local efficiency and higher assortativity than controls. Concerning local network topological properties, patients had reduced local efficiency (left lateral orbital gyrus and pallidum), increased clustering (left lateral orbital gyrus), increased nodal strength (right anterior orbital gyrus), and reduced nodal strength (left amygdala). SS-16 test score was negatively correlated with clustering of whole-brain WM in the COVID-19 group. Thus, patients with OD after COVID-19 had relevant WM network dysfunction with increased connectivity in the parietal sensory cortex. Reduced integration and increased segregation are observed within olfactory-related brain areas might be due to compensatory plasticity mechanisms devoted to recovering olfactory function.

Parkinson's Disease-Cognitive Rating Scale (PD-CRS): Normative Data and Mild Cognitive Impairment Assessment in Brazil.

Background: The Parkinson's Disease-Cognitive Rating Scale (PD-CRS) assesses posterior-cortical and frontal-subcortical cognitive functioning and distinguishes mild cognitive impairment in Parkinson's disease (PD-MCI); however, it was not evaluated in Brazil. Objectives: To investigate PD-CRS's reliability, validity, normative data, and accuracy for PD-MCI screening in Brazil. Methods: The effects of age, education, and sex on PD-CRS scores were explored. The instrument was tested in 714 individuals (53% female, 21-94 years), with a broad range of education and no neurodegenerative disorder. Trail Making, Consonant Trigrams, Five-Point, and semantic fluency tests were administered for comparison. A second study enrolled patients with PD and intact cognition (n = 44, 59.75 ± 10.79 years) and with PD-MCI (n = 25, 65.76 ± 10.33 years) to investigate criterion validity. PD-CRS subtests were compared with the Cambridge Automated Neuropsychological Battery memory and executive tasks. Results: PD-CRS was unidimensional and reliable (McDonald's ω = 0.83). Using robust multiple regressions, age, and education predicted the total and derived scores in the normative sample. At the 85-point cutoff, PD-MCI was detected with 68% sensitivity and 86% specificity (area under the curve = 0.870). PD-CRS scores strongly correlated with executive and verbal/visual memory tests in both normative and clinical samples. Conclusions: This study investigated the applicability of PD-CRS in the Brazilian context. The scale seems helpful in screening for PD-MCI, with adequate internal consistency and construct validity. The PD-CRS variance is influenced by age and educational level, a critical issue for cognitive testing in countries with educational and cultural heterogeneity.

Evaluation of the Cutaneous Silent Period in a Healthy Brazilian Population.

PURPOSE: To establish cutaneous silent period (CSP) normative values and investigate the variables that may influence them. METHODS: We tested 41 healthy subjects. All subjects underwent nerve conduction studies, and we evaluated the CSP in both arms. RESULTS: Four subjects did not have CSP and were excluded. The analyses were performed in the healthy group composed of 23 women and 14 men, with a mean age of 35 (range, 19-64) years. The CSP median duration was 23.2 milliseconds (ms), with 2 to 98th percentile at 11.3 and 48.7 ms. The median onset latency was 87.9 (range, 72.9-109) ms, and the median end latency was 112 (range, 93.8-138) ms. The CSP onset latency positively correlated with height, whereas CSP end latency and duration were weakly but significantly associated with age. Some measurements of ulnar nerve conduction study also correlated with CSP measures. The interrater coefficients for the primary measures of onset and end latency demonstrates the reproducibility of the method. CONCLUSIONS: The CSP with the fifth digit stimulation and recording from the abductor digiti minimi muscle is a valid diagnostic tool that can be used in clinical practice.

Floor and ceiling effects on the Montreal Cognitive Assessment in patients with Parkinson's disease in Brazil / Efeitos solo e teto na Avaliação Cognitiva de Montreal em pacientes com doença de Parkinson no Brasil

ABSTRACT Parkinson's disease (PD) is a common neurodegenerative disease associated with cognitive impairment. The Montreal Cognitive Assessment (MoCA) has been used as a recommended global cognition scale for patients with PD, but there are some concerns about its application, partially due to the floor and ceiling effects. Objective: To explore the floor and ceiling effects on the MoCA in patients with PD in Brazil. Methods: Cross-sectional study with data from patients with PD from five Brazilian Movement Disorders Clinics, excluding individuals with a possible diagnosis of dementia. We analyzed the total score of the MoCA, as well as its seven cognitive domains. The floor and ceiling effects were evaluated for the total MoCA score and domains. Multivariate analyses were performed to detect factors associated with floor and ceiling effects. Results: We evaluated data from 366 patients with PD and approximately 19% of individuals had less than five years of education. For the total MoCA score, there was no floor or ceiling effect. There was a floor effect in the abstraction and delayed memory recall domains in 20% of our sample. The ceiling effect was demonstrated in all domains (80.8% more common in naming and 89% orientation), except delayed recall. Education was the main factor associated with the floor and ceiling effects, independent of region, sex, age at evaluation, and disease duration. Conclusion: The floor and ceiling effects are present in specific domains of the MoCA in Brazil, with a strong impact on education. Further adaptations of the MoCA structure for underrepresented populations may reduce these negative effects.

RESUMO A doença de Parkinson (DP) é uma doença neurodegenerativa comum associada ao declínio cognitivo. A Avaliação Cognitiva de Montreal (Montreal Cognitive Assessment — MoCA) tem sido usada como uma escala de cognição global recomendada para pacientes com DP, mas existem algumas preocupações sobre sua aplicação, em parte pelos efeitos solo e teto. Objetivo: Explorar os efeitos solo e teto na MoCA em pacientes com DP no Brasil. Métodos: Estudo transversal com dados de pacientes com DP oriundos de cinco Clínicas de Distúrbios de Movimento no Brasil, excluindo-se pessoas com possível diagnóstico de demência. Nós analisamos a pontuação total da MoCA, assim como a de seus sete domínios cognitivos. Os efeitos solo e teto foram avaliados para a pontuação total da MoCA e seus domínios. Foram feitas análises multivariadas para a detecção de fatores associados os efeitos solo e teto. Resultados: Nós avaliamos dados de 366 pacientes com DP, e aproximadamente 19% das pessoas tinham menos que cinco anos de escolaridade. Para a pontuação total do MoCA, não houve efeito solo ou teto. Houve efeito solo nos domínios abstração e memória de evocação tardia em 20% de nossa amostra. O efeito teto foi demonstrado em todos os domínios (80,8% mais comum em nomeação e 89% orientação), com exceção de memória de evocação tardia. A educação foi o principal fator associado aos efeitos solo e teto, independentemente de região, sexo, idade na avaliação e duração da doença. Conclusão: Os efeitos solo e teto estão presentes em domínios específicos da MoCA no Brasil, com forte impacto da educação. Adaptações adicionais à estrutura da MoCA para populações vulneráveis podem reduzir esses efeitos negativos.

Brain microstructural changes and fatigue after COVID-19.

Background: Fatigue and cognitive complaints are the most frequent persistent symptoms in patients after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This study aimed to assess fatigue and neuropsychological performance and investigate changes in the thickness and volume of gray matter (GM) and microstructural abnormalities in the white matter (WM) in a group of patients with mild-to-moderate coronavirus disease 2019 (COVID-19). Methods: We studied 56 COVID-19 patients and 37 matched controls using magnetic resonance imaging (MRI). Cognition was assessed using Montreal Cognitive Assessment and Cambridge Neuropsychological Test Automated Battery, and fatigue was assessed using Chalder Fatigue Scale (CFQ-11). T1-weighted MRI was used to assess GM thickness and volume. Fiber-specific apparent fiber density (FD), free water index, and diffusion tensor imaging data were extracted using diffusion-weighted MRI (d-MRI). d-MRI data were correlated with clinical and cognitive measures using partial correlations and general linear modeling. Results: COVID-19 patients had mild-to-moderate acute illness (95% non-hospitalized). The average period between real-time quantitative reverse transcription polymerase chain reaction-based diagnosis and clinical/MRI assessments was 93.3 (±26.4) days. The COVID-19 group had higher total CFQ-11 scores than the control group (p < 0.001). There were no differences in neuropsychological performance between groups. The COVID-19 group had lower FD in the association, projection, and commissural tracts, but no change in GM. The corona radiata, corticospinal tract, corpus callosum, arcuate fasciculus, cingulate, fornix, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, superior longitudinal fasciculus, and uncinate fasciculus were involved. CFQ-11 scores, performance in reaction time, and visual memory tests correlated with microstructural changes in patients with COVID-19. Conclusions: Quantitative d-MRI detected changes in the WM microstructure of patients recovering from COVID-19. This study suggests a possible brain substrate underlying the symptoms caused by SARS-CoV-2 during medium- to long-term recovery.

Persistent, new-onset symptoms and mental health complaints in Long COVID in a Brazilian cohort of non-hospitalized patients.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections lead to acute- and chronic Long COVID (LC) symptoms. However, few studies have addressed LC sequelae on brain functions. This study was aimed to examine if acute symptoms of coronavirus disease 2019 (COVID-19) would persist during LC, and if memory problems would be correlated with sleep, depressive mood, or anxious complaints. METHODS: Our work followed a cohort of 236 patients from two public hospitals of the Federal District in mid-western Brazil. Patients' interviews checked for clinical symptoms during acute and LC (5-8 months after real-time reverse transcription polymerase chain reaction, RT-qPCR). RESULTS: Most cases were non-hospitalized individuals (86.3%) with a median age of 41.2 years. While myalgia (50%), hyposmia (48.3%), and dysgeusia (45.8%) were prevalent symptoms in acute phase, fatigue (21.6%) followed by headache (19.1%) and myalgia (16.1%) commonly occurred during LC. In LC, 39.8% of individuals reported memory complaints, 36.9% felt anxious, 44.9% felt depressed, and 45.8% had sleep problems. Furthermore, memory complaints were associated with sleep problems (adjusted OR 3.206; 95% CI 1.723-6.030) and depressive feelings (adjusted OR 3.981; 95% CI 2.068-7.815). CONCLUSIONS: The SARS-CoV-2 infection leads to persistent symptoms during LC, in which memory problems may be associated with sleep and depressive complaints.

New-Onset Movement Disorders Associated with COVID-19.

Introduction: Movement disorders are increasingly described in hospitalized and milder cases of SARS-CoV-2 infection, despite a very low prevalence compared to the total patients. Methods: We reviewed the scientific literature published in English, spanning from the initial descriptions of COVID-19 until January 25, 2021, in the PubMed/MEDLINE database. Results: We identified 93 new-onset movement disorders cases (44 articles) from 200 papers screened in the database or reference lists. Myoclonus was present in 63.4% (n = 59), ataxia in 38.7% (n = 36), action/postural tremor in 10.8% (n = 10), rigid-akinetic syndrome in 5.38% (n = 5), oculomotor abnormalities in 20.4% (n = 19), catatonia in 2.1% (n = 2), dystonia in 1.1% (n = 1), chorea in 1.1% (n = 1), functional (psychogenic) movement disorders in 3.2% (n = 3) of the reported COVID-19 cases with any movement disorder. Encephalopathy was a common association (n = 37, 39.78%). Discussion: Comprehensive neurophysiological, clinical, and neuroimaging descriptions of movement disorders in the setting of SARS-CoV-2 infection are still lacking, and their pathophysiology may be related to inflammatory, postinfectious, or even indirect mechanisms not specific to SARS-CoV-2, such as ischemic-hypoxic brain insults, drug effects, sepsis, kidney failure. Cortical/subcortical myoclonus, which the cited secondary mechanisms can largely cause, seems to be the most common hyperkinetic abnormal movement, and it might occur in association with encephalopathy and ataxia. Conclusion: This brief review contributes to the clinical description of SARS-CoV-2 potential neurological manifestations, assisting clinical neurologists in identifying features of these uncommon syndromes as a part of COVID-19 symptomatology. Highlights: - Movement disorders are probably uncommon neurological manifestations in SARS-CoV-2 infection;- Myoclonus is the most reported movement disorder associated with COVID-19, its clinical complications or pharmacological management;- The pathophysiology is yet not well-understood but can include systemic inflammation, autoimmune mechanisms, or hypoxia.

microRNA signatures in prodromal REM sleep behavior disorder and early Parkinson's disease as noninvasive biomarkers.

The flow of gene expression or "The central dogma of molecular biology": DNA - RNA - protein, proposed by Watson & Crick sixty years ago, is a tightly controlled cell process. In the middle of this journey, the mRNA molecule is regulated by "RNA interference" (RNAi), a posttranscriptional gene silencing mechanism. A microRNA is an endogenous short double-stranded RNA that down-regulates hundreds of mRNAs by RNAi, maintaining healthy cell physiology. In contrast, aberrant expressions of microRNAs play a role in Parkinson's disease (PD) pathogenesis. The damage may start at an early period of brain degeneration, in the non-motor or "prodromal" stage, where autonomic, mood and sleep changes are often manifested. REM-sleep behavior disorder (RBD) is the prodromal manifestation with the highest odds for conversion into PD, thereby a valuable phenotype for disease prediction. The present review focuses on microRNAs' role in the pathogenesis of PD and RBD, summarizing the state-of-the-art of these RNA molecules as noninvasive biomarkers for non-motor prodromal (RBD) and early PD.

Cognitive impairment in Parkinson's disease: A clinical and pathophysiological overview.

Cognitive dysfunction in Parkinson's disease (PD) has received increasing attention, and, together with other non-motor symptoms, exert a significant functional impact in the daily lives of patients. This article aims to compile and briefly summarize selected published data about clinical features, cognitive evaluation, biomarkers, and pathophysiology of PD-related dementia (PDD). The literature search included articles indexed in the MEDLINE/PubMed database, published in English, over the last two decades. Despite significant progress on clinical criteria and cohort studies for PD-mild cognitive impairment (PD-MCI) and PDD, there are still knowledge gaps about its exact molecular and pathological basis. Here we overview the scientific literature on the role of functional circuits, neurotransmitter systems (monoaminergic and cholinergic), basal forebrain, and brainstem nuclei dysfunction in PD-MCI. Correlations between neuroimaging and cerebrospinal fluid (CSF) biomarkers, clinical outcomes, and pathological results are described to aid in uncovering the neurodegeneration pattern in PD-MCI and PDD.

How can neurophysiological studies help with movement disorders characterization in clinical practice? A review.

BACKGROUND: Neurophysiological studies are ancillary tools to better understand the features and nature of movement disorders. Electromyography (EMG), together with electroencephalography (EEG) and accelerometer, can be used to evaluate a hypo and hyperkinetic spectrum of movements. Specific techniques can be applied to better characterize the phenomenology, help distinguish functional from organic origin and assess the most probable site of the movement generator in the nervous system. OBJECTIVE: We intend to provide an update for clinicians on helpful neurophysiological tools to assess movement disorders in clinical practice. METHODS: Non-systematic review of the literature published up to June 2019. RESULTS: A diversity of protocols was found and described. These include EMG analyses to define dystonia, myoclonus, myokymia, myorhythmia, and painful legs moving toes pattern; EMG in combination with accelerometer to study tremor; and EEG-EMG to study myoclonus. Also, indirect measures of cortical and brainstem excitability help to describe and diagnose abnormal physiology in Parkinson's disease, atypical parkinsonism, dystonia, and myoclonus. CONCLUSION: These studies can be helpful for the diagnosis and are usually underutilized in neurological practice.

How can neurophysiological studies help with movement disorders characterization in clinical practice? A review / Como os exames neurofisiológicos podem ajudar na caracterização dos transtornos do movimento na prática clínica? Uma revisão

ABSTRACT Background: Neurophysiological studies are ancillary tools to better understand the features and nature of movement disorders. Electromyography (EMG), together with electroencephalography (EEG) and accelerometer, can be used to evaluate a hypo and hyperkinetic spectrum of movements. Specific techniques can be applied to better characterize the phenomenology, help distinguish functional from organic origin and assess the most probable site of the movement generator in the nervous system. Objective: We intend to provide an update for clinicians on helpful neurophysiological tools to assess movement disorders in clinical practice. Methods: Non-systematic review of the literature published up to June 2019. Results: A diversity of protocols was found and described. These include EMG analyses to define dystonia, myoclonus, myokymia, myorhythmia, and painful legs moving toes pattern; EMG in combination with accelerometer to study tremor; and EEG-EMG to study myoclonus. Also, indirect measures of cortical and brainstem excitability help to describe and diagnose abnormal physiology in Parkinson's disease, atypical parkinsonism, dystonia, and myoclonus. Conclusion: These studies can be helpful for the diagnosis and are usually underutilized in neurological practice.

RESUMO Introdução: Os estudos neurofisiológicos são métodos auxiliares para compreender melhor as características e a natureza dos distúrbios do movimento. A eletromiografia (EMG), em associação com o eletroencefalograma (EEG) e o acelerômetro, podem ser utilizados para avaliar um espectro de movimentos hipo e hipercinéticos. Técnicas específicas podem ser aplicadas para melhor caracterizar a fenomenologia, ajudar a distinguir a origem psicogênica da orgânica e avaliar o local mais provável de geração do movimento no sistema nervoso. Objetivo: Pretendemos fornecer ao clínico uma atualização sobre ferramentas neurofisiológicas úteis para avaliar distúrbios do movimento na prática clínica. Métodos: Revisão não sistemática da literatura publicada até junho de 2019. Resultados: Uma diversidade de protocolos foi encontrada e descrita. Dentre eles, inclui-se o uso de EMG para a definição do padrão de distonia, mioclonia, mioquimia, miorritmia e painfull legs moving toes, além do uso de EMG em associação ao acelerômetro para avaliar tremor e, em associação ao EEG para avaliar mioclonia. Ademais, técnicas para medida indireta de excitabilidade cortical e do tronco encefálico ajudam a descrever e diagnosticar a fisiologia anormal da doença de Parkinson, parkinsonismo atípico, distonia e mioclonia. Conclusão: Esses estudos podem ser úteis para o diagnóstico e geralmente são subutilizados na prática neurológica.

Leading RNA Interference Therapeutics Part 1: Silencing Hereditary Transthyretin Amyloidosis, with a Focus on Patisiran.

In 2018, patisiran was the first-ever RNA interference (RNAi)-based drug approved by the US Food and Drug Administration. Now pharmacology textbooks may include a new drug class that results in the effect first described by Fire and Mello 2 decades ago: post-transcriptional gene silencing by a small-interfering RNA (siRNA). Patients with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) present with mutations in the transthyretin (TTR) gene that lead to the formation of amyloid deposits in peripheral nerves and heart. The disease may also affect the eye and central nervous system. The formulation of patisiran comprises the RNAi drug encapsulated into a nanoparticle especially developed to deliver the anti-TTR siRNA into the main TTR producer: the liver. Hepatic cells contain apolipoprotein E receptors that recognize ApoE proteins opsonized in the lipid carrier and internalize the drug by endocytosis. Lipid vesicles are disrupted in the cell cytoplasm, and siRNAs are free to trigger the RNAi-based TTR gene silencing. The silencing process involves the binding of siRNA guide strand to 3'-untranslated region sequence of both mutant and wild-type TTR messenger RNA, which culminates in the TTR mRNA cleavage by the RNA-induced silencing complex (RISC) as the first biochemical drug effect. Patisiran 0.3 mg/kg is administered intravenously every 3 weeks. Patients require premedication with anti-inflammatory drugs and antagonists of histamine H1 and H2 receptors to prevent infusion-related reactions and may require vitamin A supplementation. Following patisiran treatment, TTR knockdown remained stable for at least 2 years. Adverse effects were mild to moderate with unchanged hematological, renal, or hepatic parameters. No drug-related severe adverse effects occurred in a 24-month follow-up phase II open-label extension study. At the recommended dosage of patisiran, Cmax and AUC values (mean ± standard deviation) were 7.15 ± 2.14 µg/mL and 184 ± 159 µg·h/mL, respectively. The drug showed stability in circulation with > 95% encapsulated in lipid particles. Metabolization occurred by ribonuclease enzymes, with less than 1% excreted unchanged in the urine. Patisiran ameliorated neuropathy impairment according to the modified Neuropathy Impairment Score + 7 analysis of the phase III study. The Norfolk Quality of Life-Diabetic Neuropathy score and gait speed improved in 51% of the patisiran-treated group in 18 months. Additionally, the modified body mass index showed positive outcomes. Altogether, the data across phase I-III clinical trials points to patisiran as an effective and safe drug for the treatment of hATTR amyloidosis. It is hoped that real-world data from a larger number of patients treated with patisiran will confirm the effectiveness of this first-approved siRNA-based drug.

Leading RNA Interference Therapeutics Part 2: Silencing Delta-Aminolevulinic Acid Synthase 1, with a Focus on Givosiran.

In November 2019 givosiran became the second small interfering RNA (siRNA)-based drug to receive US Food and Drug Administration (FDA) approval, it has been developed for the treatment of acute intermittent porphyria (AIP), a disorder characterized by life-threatening acute neurovisceral attacks. The porphyrias are a group of disorders in which enzymatic deficiencies in heme production lead to toxic accumulation of delta-aminolevulinic acid (ALA) and porphobilinogen (PBG), which are involved in the neurovisceral attacks. Givosiran acts as a conventional siRNA to trigger RNA interference (RNAi)-mediated gene silencing on delta-ALA synthase 1 (ALAS1), thus returning ALA and PBG metabolites to the physiological level to attenuate further neurotoxicity. Givosiran makes use of a new hepatic-delivery system that conjugates three GalNac (N-acetylgalactosamine) molecules to the siRNA passenger strand. GalNac binds to the liver asialoglycoprotein receptor, favoring the internalization of these GalNac-conjugated siRNAs into the hepatic cells. In a phase I study, subcutaneous monthly administration of givosiran 2.5 mg/kg reduced > 90% of ALA and PBG content. This siRNA is being analyzed in ENVISION (NCT03338816), a phase III, multicenter, placebo-controlled randomized controlled trial. In preliminary results, givosiran achieved clinical endpoints for AIP, reducing urinary ALA levels, and presented a safety profile that enabled further drug development. The clinical performance of givosiran revealed that suppression of ALAS1 by GalNac-decorated siRNAs represents an additional approach for the treatment of patients with AIP that manifests recurrent acute neurovisceral attacks.

Is transcranial sonography useful for diagnosing Parkinson's disease in clinical practice?

OBJECTIVE: Transcranial sonography (TCS) is an emerging ancillary examination for diagnosing Parkinson's disease (PD). OBJECTIVE: To evaluate TCS features in patients with PD and its mimics, and establish their accuracy in predicting the final clinical diagnosis after follow-up. METHODS: We retrospectively studied 85 patients with an initial clinical suspicion of PD, atypical parkinsonism or essential tremor, all of whom underwent TCS. Two specialists reviewed the follow-up clinical visit records and determined the final clinical diagnosis. The accuracy analysis of the TCS was determined using Bayesian statistical methods. RESULTS: The finding of substantia nigra hyperechogenicity (> 20 mm2) showed high sensitivity (93.4%) and specificity (86.6%). The positive likelihood ratio showed 6.93-fold greater odds for diagnosing PD than an alternative condition when this finding was present. CONCLUSIONS: This study revealed the practical usefulness of TCS in differentiating PD from its prevalent mimics when the clinical diagnosis was initially unclear.