Face and content validation of the amyotrophic lateral sclerosis—Bulbar dysfunction index (ALS-BDI)

PurposeEarly detection and tracking of bulbar dysfunction in amyotrophic lateral sclerosis (ALS) are critical for directing management of the disease. Existing physiological assessments of bulbar dysfunction are often inaccessible and cost-prohibitive for clinical application. Existing clinical assessments are limited. The overall goal of our research is to develop a brief and reliable, clinician-administered assessment tool, the ALS Bulbar Dysfunction Index (ALS-BDI) to evaluate bulbar dysfunction. The aim of this study was to establish content and face validity of the ALS-BDI through item generation and reduction, including item scoring.MethodsThe design of the ALS-BDI followed guidelines outlined by the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN). The design stage of the ALS-BDI involved two steps: (Step 1) the generation of candidate items from a literature review of commonly used clinical tools, and selection of items following a review of item reliability and item relevance and expert consensus; (Step 2) the assessment of their content and face validity via online survey feedback from experts (n = 35). The initial design was followed by a semi-structured cognitive interview with Speech-Language Pathologists (n = 5) to finalize a testable draft of the instrument.ResultsTwo drafts of the ALS-BDI were developed. The first draft contained 48 items, after a review of existing clinical tools for their relevance to bulbar dysfunction in ALS. Of the 48 items, 35 items were retained after surveying experts and clinician users for their relevance, feasibility, interpretability, and appropriateness. The second draft of the ALS-BDI contained 37 items, due to one item splitting, based on users cognitive interviews.ConclusionsThe ALS-BDI described in this study aims to provide a brief and reliable, clinician-administered assessment tool to evaluate bulbar dysfunction in patients with ALS. Future research will evaluate the psychometric properties of this tool including its reliability, validity, and responsiveness to change over time

Investigating the contribution of white matter hyperintensities and cortical thickness to empathy in neurodegenerative and cerebrovascular diseases

Change in empathy is an increasingly recognised symptom of neurodegenerative diseases and contributes to caregiver burden and patient distress. Empathy impairment has been associated with brain atrophy but its relationship to white matter hyperintensities (WMH) is unknown. We aimed to investigate the relationships amongst WMH, brain atrophy, and empathy deficits in neurodegenerative and cerebrovascular diseases. Five hundred thirteen participants with Alzheimer’s disease/mild cognitive impairment, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), Parkinson’s disease, or cerebrovascular disease (CVD) were included. Empathy was assessed using the Interpersonal Reactivity Index. WMH were measured using a semi-automatic segmentation and FreeSurfer was used to measure cortical thickness. A heterogeneous pattern of cortical thinning was found between groups, with FTD showing thinning in frontotemporal regions and CVD in left superior parietal, left insula, and left postcentral. Results from both univariate and multivariate analyses revealed that several variables were associated with empathy, particularly cortical thickness in the fronto-insulo-temporal and cingulate regions, sex (female), global cognition, and right parietal and occipital WMH. Our results suggest that cortical atrophy and WMH may be associated with empathy deficits in neurodegenerative and cerebrovascular diseases. Future work should consider investigating the longitudinal effects of WMH and atrophy on empathy deficits in neurodegenerative and cerebrovascular diseases

Caregiving concerns and clinical characteristics across neurodegenerative and cerebrovascular disorders in the Ontario neurodegenerative disease research initiative

Objectives: Caregiving burdens are a substantial concern in the clinical care of persons with neurodegenerative disorders. In the Ontario Neurodegenerative Disease Research Initiative, we used the Zarit\u27s Burden Interview (ZBI) to examine: (1) the types of burdens captured by the ZBI in a cross-disorder sample of neurodegenerative conditions (2) whether there are categorical or disorder-specific effects on caregiving burdens, and (3) which demographic, clinical, and cognitive measures are related to burden(s) in neurodegenerative disorders?. Methods/Design: N = 504 participants and their study partners (e.g., family, friends) across: Alzheimer\u27s disease/mild cognitive impairment (AD/MCI; n = 120), Parkinson\u27s disease (PD; n = 136), amyotrophic lateral sclerosis (ALS; n = 38), frontotemporal dementia (FTD; n = 53), and cerebrovascular disease (CVD; n = 157). Study partners provided information about themselves, and information about the clinical participants (e.g., activities of daily living (ADL)). We used Correspondence Analysis to identify types of caregiving concerns in the ZBI. We then identified relationships between those concerns and demographic and clinical measures, and a cognitive battery. Results: We found three components in the ZBI. The first was “overall burden” and was (1) strongly related to increased neuropsychiatric symptoms (NPI severity r = 0.586, NPI distress r = 0.587) and decreased independence in ADL (instrumental ADLs r = −0.566, basic ADLs r = −0.43), (2) moderately related to cognition (MoCA r = −0.268), and (3) showed little-to-no differences between disorders. The second and third components together showed four types of caregiving concerns: current care of the person with the neurodegenerative disease, future care of the person with the neurodegenerative disease, personal concerns of study partners, and social concerns of study partners. Conclusions: Our results suggest that the experience of caregiving in neurodegenerative and cerebrovascular diseases is individualized and is not defined by diagnostic categories. Our findings highlight the importance of targeting ADL and neuropsychiatric symptoms with caregiver-personalized solutions

Targeted copy number variant identification across the neurodegenerative disease spectrum

Background: Although genetic factors are known to contribute to neurodegenerative disease susceptibility, there remains a large amount of heritability unaccounted for across the diagnoses. Copy number variants (CNVs) contribute to these phenotypes, but their presence and influence on disease state remains relatively understudied. Methods: Here, we applied a depth of coverage approach to detect CNVs in 80 genes previously associated with neurodegenerative disease within participants of the Ontario Neurodegenerative Disease Research Initiative (n = 519). Results: In total, we identified and validated four CNVs in the cohort, including: (1) a heterozygous deletion of exon 5 in OPTN in an Alzheimer\u27s disease participant; (2) a duplication of exons 1–5 in PARK7 in an amyotrophic lateral sclerosis participant; (3) a duplication of \u3e3 Mb, which encompassed ABCC6, in a cerebrovascular disease (CVD) participant; and (4) a duplication of exons 7–11 in SAMHD1 in a mild cognitive impairment participant. We also identified 43 additional CNVs that may be candidates for future replication studies. Conclusion: The identification of the CNVs suggests a portion of the apparent missing heritability of the phenotypes may be due to these structural variants, and their assessment is imperative for a thorough understanding of the genetic spectrum of neurodegeneration

Estudo da expressão gênica nas células do sangue periférico de pacientes com ataxia de friedreich

Friedreich Ataxia (FRDA) is the most common autosomal recessive ataxia characterized by a combination of neurological involvement, cardiomyopathy, skeletal and glucose metabolism disturbances. FRDA is caused by mutations in FXN gene, that results in reduction of mRNA and protein levels of Frataxin. Previous microarray and real-time quantitative PCR (qPCR) studies showed that the downregulation of FXN is associated with a complex gene expression profile. However, these studies showed a wide variability in the subset of genes with altered expression among tissues and models. Genes differentially expressed in peripheral blood cells (PBCs) could potentially help in the understanding of FRDA pathophysiology and also function as reliable disease biomarkers obtained from an easily accessible tissue, which could have implications in clinical practice. This study aimed to validate by qPCR the expression of 26 genes, revealed as differentially expressed by other studies, using PBCs of 11 FRDA patients compared to 11 healthy controls. We found a robust downregulation of FXN, but no statistically significant differences were found between FRDA and controls for the remaining genes. Except for FXN, our study did not find a differential gene expression profile in PBCs of FRDA patients and a reliable gene expression profile biomarker obtained from an easily accessible tissue remains unclear.A Ataxia de Friedreich (FRDA) é a ataxia hereditária mais frequente em todo o mundo, caracterizada por ataxia cerebelar, alteração proprioceptiva, arreflexia, presença do sinal de Babinski e disartria, além envolvimento de outros sistemas, como miocardiopatia, diabetes mellitus, escoliose e pes cavus. A FRDA é causada por mutações no gene FXN, que resulta na redução da produção do RNA mensageiro e da proteína frataxina. Estudos publicados previamente usando microarray e PCR quantitativo em tempo real (qPCR) mostraram que a redução da expressão do FXN está associada à alteração no perfil de expressão de diferentes genes. Entretanto, estes estudos usaram modelos e tecidos distintos e apontaram uma grande variabilidade entre os genes diferencialmente expressos. Considerando que esta questão permanece em aberto, um conjunto de genes com expressão alterada de forma reprodutível e consistente em um tecido de acesso minimamente invasivo, como as células do sangue periférico (CSP), pode contribuir para a ampliação do entendimento da fisiopatologia da FRDA, bem como constituir um biomarcador útil para a prática clínica, como o seu uso para monitorização dos efeitos de novas abordagens terapêuticas. O objetivo deste estudo foi avaliar, através do método de qPCR, se as alterações no perfil de expressão de 26 genes apontados por estes estudos prévios são reprodutíveis nas CSP de uma amostra de 11 pacientes com fenótipo típico e diagnóstico molecular confirmado de FRDA, comparados com 11 controles sadios. Nós encontramos uma redução robusta na expressão do FXN e diferenças sem significância estatística na expressão dos outros genes nos pacientes com FRDA em relação aos controles. Com exceção do FXN, nosso estudo não validou um perfil de genes diferencialmente expressos nas CSP de pacientes com FRDA, permanecendo indeterminado o uso dos mesmos como biomarcadores em um tecido de fácil acesso na prática clínica.Dados abertos - Sucupira - Teses e dissertações (2013 a 2016

Impact of reference electrode position on motor unit number estimation (MUNE) in the tibialis anterior muscle using MScanFit: test-retest reliability

Compound muscle action potential (CMAP) scans were done using the MScanFit MUNE protocol, stimulating the fibular nerve and monitoring the response from the tibialis anterior muscle. There are two cohorts of data: 1) cohort #1 was collected with the reference electrode in the position mandated by the MScanFit Multicenter protocol (designated M1 position), and 2) cohort #2 was collected in a repeated measures design using three different positions for the reference electrode (M1, R1 and A3). All participants came for two visits (V1 & V2) separated by an interval of 7-14 days. The two outcome measures in the data are: 1) maximum CMAP in millivots, and 2) motor unit number estimates (MUNE) derived from the MScanFit optimization process. The Excel file contains anonymized individual participant data (IPD).</p

Neuromodulation Strategies in Post-Traumatic Stress Disorder: From Preclinical Models to Clinical Applications

Post-traumatic stress disorder (PTSD) is an often debilitating disease with a lifetime prevalence rate between 5&#8315;8%. In war veterans, these numbers are even higher, reaching approximately 10% to 25%. Although most patients benefit from the use of medications and psychotherapy, approximately 20% to 30% do not have an adequate response to conventional treatments. Neuromodulation strategies have been investigated for various psychiatric disorders with promising results, and may represent an important treatment option for individuals with difficult-to-treat forms of PTSD. We review the relevant neurocircuitry and preclinical stimulation studies in models of fear and anxiety, as well as clinical data on the use of transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), and deep brain stimulation (DBS) for the treatment of PTSD