Primary lateral sclerosis natural history study - planning, designing, and early enrollment.

Introduction/Aims. Primary lateral sclerosis (PLS) is exceedingly rare and has been an enigmatic disease. Recent progress has drastically changed this perception, with early biomarkers being investigated and potential medications for PLS emerging at the preclinical stage. The aim of this paper is to describe a study of PLS natural history and discuss the limitations and proposed solutions to the study of a rare and slowly progressive disease. Methods. The PLS Natural History Study is a 30-site, 24-month, prospective study that is supported by multiple funding sources. The study aims to enroll 50 early PLS (disease duration ≤4 years) and 50 definite PLS (disease duration 4 to 15 years) participants using modified PLS Diagnostic Criteria. Smartphone-based assessments including semi-quantitative and quantitative measures and patient-reported outcomes are utilized. In-person quantitative measures are also completed during site visits. The change in the PLS Functional Rating Scale score is the primary outcome. The study utilizes the NeuroBANK® patient-centric data capture and management platform. The biostatistical analysis plan has been developed. Results. In one year, 28 participants have been recruited. Enrollment has been much slower than anticipated due to the COVID-19 pandemic, the rarity of PLS, and potential study competition for internal resources from ALS clinical trials. Discussion. We discuss the need for more innovative methods to enroll and study individuals with such rare diseases and propose a number of mechanisms by which more efficient enrollment could be facilitated.

Embedded Palliative Care for Amyotrophic Lateral Sclerosis: A Pilot Program and Lessons Learned.

Background and Objectives: Palliative care (PC) is recommended for people with amyotrophic lateral sclerosis (ALS), but there is scant literature about how to best provide this care. We describe the structure and impact of a pilot program that integrates longitudinal, interdisciplinary PC into the care of patients with ALS. Methods: Observational cohort study of patients with ALS referred to outpatient PC and seen for at least 3 PC visits October 2017-July 2020. Results: Fifty-five patients met the inclusion criteria. Three-quarters (74.5%) were Caucasian, and 78.2% spoke English. Patients were referred for advance care planning (58.2%), support for patient/family (52.7%), and symptoms other than pain (50.9%). Patients had a mean of 5 scheduled PC visits, the majority occurred by video. A PC physician, nurse, social worker, and chaplain addressed pain (for 43.6% of patients), nonpain symptoms (94.5%), psychosocial distress (78.2%), spiritual concerns (29.1%), care planning (96.4%), and supported family caregivers (96.4%). With PC, the rate of completion of advance directives increased from 16.4% to 36.4% (p = 0.001) and Physician Orders for Life-Sustaining Treatment forms from 10.9% to 63.6% (p < 0.001). Of the 27 patients who died, 77.8% used hospice, typically for more than 30 days. Eleven patients obtained aid-in-dying prescriptions, and 8 took these medications, accounting for 29.6% of the deaths. Discussion: Integrating longitudinal, interdisciplinary PC into the care of patients with ALS is feasible, addresses needs in multiple domains, and is associated with increased rates of advance care planning. Controlled studies are needed to further elucidate the impact of PC on patients with ALS, their families, and clinicians.

ALS patient and caregiver attitudes toward physician-hastened death in California.

INTRODUCTION/AIMS: Since 2016, six states have legalized physician-hastened death (PHD). Neuromuscular disorders, including amyotrophic lateral sclerosis (ALS), are common diagnoses for patients who use PHD, but how patients with ALS view PHD in California has not been systematically studied. We aimed to quantify how many patients with ALS and their caregivers have considered PHD and to assess reasons to consider using or not using it. METHODS: This is a cross-sectional study at one ALS center surveying patients with ALS and their caregivers. Data on disease characteristics, demographics, quality of life, and depression were also collected. Descriptive statistics were used to analyze the data. Qualitative data were also collected and analyzed. Patients were followed up longitudinally to assess if they died or if they used PHD. RESULTS: A small majority of ALS patients surveyed had considered or would consider using PHD (16/30). Patients most commonly described having intolerable symptoms, being a burden on their loved ones, and losing independence as reasons to consider using PHD. Many patients shared that "their life has purpose" and "they are making the most of their lives" as to why they are not considering PHD. Considering PHD was not related to disease severity or depression. On longitudinal follow-up, 10 of the 30 patients have died, and none have used PHD. DISCUSSION: Pursuing PHD is a personal decision for each individual patient. This study shows that considering PHD is relatively common in ALS patients, independent of disease severity or presence of depression.

Current Status and Future Strategies for Mentoring Women in Neurology.

The American Academy of Neurology's (AAN) 2017 Gender Disparity Report identified improving mentorship as a key intervention to fill the leadership and pay gaps for women in neurology. Here we summarize the literature on mentoring women, provide an outline of ideal components of programs geared toward closing gender gaps, and present a mentoring program for AAN members. The strategies discussed share similarities with those for closing gaps related to race, ethnicity, and religion. Developing effective mentorship and sponsorship programs is essential to ensure a sufficiently diverse pool of academic faculty and private practitioners and to establish equal representation in leadership roles in this field.

Comprehensive cell type decomposition of circulating cell-free DNA with CelFiE.

Circulating cell-free DNA (cfDNA) in the bloodstream originates from dying cells and is a promising noninvasive biomarker for cell death. Here, we propose an algorithm, CelFiE, to accurately estimate the relative abundances of cell types and tissues contributing to cfDNA from epigenetic cfDNA sequencing. In contrast to previous work, CelFiE accommodates low coverage data, does not require CpG site curation, and estimates contributions from multiple unknown cell types that are not available in external reference data. In simulations, CelFiE accurately estimates known and unknown cell type proportions from low coverage and noisy cfDNA mixtures, including from cell types composing less than 1% of the total mixture. When used in two clinically-relevant situations, CelFiE correctly estimates a large placenta component in pregnant women, and an elevated skeletal muscle component in amyotrophic lateral sclerosis (ALS) patients, consistent with the occurrence of muscle wasting typical in these patients. Together, these results show how CelFiE could be a useful tool for biomarker discovery and monitoring the progression of degenerative disease.

Plasma creatinine and oxidative stress biomarkers in amyotrophic lateral sclerosis.

Objective: To determine the associations between plasma creatinine (PCr), plasma uric acid (PUA), and urinary oxidative stress (OS) biomarkers with the ALSFRS-R at baseline and survival in a large epidemiological cohort study (ALS COSMOS) with a well-phenotyped patient population (N = 355).Methods: Fasting plasma and first void urine samples were obtained. PCr, PUA, urinary 8-oxo-deoxy guanosine (8-oxodG), and 15-F2t-isoprostane (IsoP) were analyzed at baseline, near the midpoint of follow-up, and at the final blood draw (before death or withdrawal from study). We estimated associations between these biomarkers and the ALSFRS-R at baseline and survival.Results: At baseline, PCr correlated with ALSFRS-R (Spearman r = 0.30), percent (%) FVC (r = 0.20), PUA (r = 0.37), and 8-oxodG (r = -0.13, all p < 0.05). Baseline PCr significantly predicted survival (adjusted hazard ratio 0.28, p < 0.001). Time to death from baseline was shortest for those in the lowest two PCr quartiles relative to the highest two quartiles. PCr and ALSFRS-R values were significantly correlated at all three time points (baseline: r = 0.29, midpoint: r = 0.23, final: r = 0.38, all p < 0.001). PCr and PUA significantly declined over time, whereas OS biomarkers significantly increased over time.Conclusions: To date, PCr predicted survival the best, compared to PUA, 8-oxodG, and IsoP. Although PCr represents the degree of muscle mass, it may also represent complex biochemical changes in ALS. Because the field has no reliable prognostic biomarkers, the importance of PCr warrants further investigation through clinical studies in ALS.

Corrigendum to "Longitudinal Screening Detects Cognitive Stability and Behavioral Deterioration in ALS Patients".

[This corrects the article DOI: 10.1155/2018/5969137.].

Revised Airlie House consensus guidelines for design and implementation of ALS clinical trials.

OBJECTIVE: To revise the 1999 Airlie House consensus guidelines for the design and implementation of preclinical therapeutic studies and clinical trials in amyotrophic lateral sclerosis (ALS). METHODS: A consensus committee comprising 140 key members of the international ALS community (ALS researchers, clinicians, patient representatives, research funding representatives, industry, and regulatory agencies) addressed 9 areas of need within ALS research: (1) preclinical studies; (2) biological and phenotypic heterogeneity; (3) outcome measures; (4) disease-modifying and symptomatic interventions; (5) recruitment and retention; (6) biomarkers; (7) clinical trial phases; (8) beyond traditional trial designs; and (9) statistical considerations. Assigned to 1 of 8 sections, committee members generated a draft set of guidelines based on a "background" of developing a (pre)clinical question and a "rationale" outlining the evidence and expert opinion. Following a 2-day, face-to-face workshop at the Airlie House Conference Center, a modified Delphi process was used to develop draft consensus research guidelines, which were subsequently reviewed and modified based on comments from the public. Statistical experts drafted a separate document of statistical considerations (section 9). RESULTS: In this report, we summarize 112 guidelines and their associated backgrounds and rationales. The full list of guidelines, the statistical considerations, and a glossary of terms can be found in data available from Dryad (appendices e-3-e-5, doi.org/10.5061/dryad.32q9q5d). The authors prioritized 15 guidelines with the greatest potential to improve ALS clinical research. CONCLUSION: The revised Airlie House ALS Clinical Trials Consensus Guidelines should serve to improve clinical trial design and accelerate the development of effective treatments for patients with ALS.

Primary progressive aphasia and the FTD-MND spectrum disorders: clinical, pathological, and neuroimaging correlates.

Objective: Behavioral variant frontotemporal dementia (bvFTD), is commonly considered the cognitive presentation of the frontotemporal dementia-motor neuron disease (FTD-MND) spectrum disorder. We evaluated the prevalence of primary progressive aphasia in a series of pathologically confirmed cases of FTD-MND spectrum. Methods: Pathologically confirmed cases of frontotemporal lobar degeneration-motor neuron disease (FTLD-MND) were obtained from the UCSF brain bank. Cases were analyzed for presence of language impairment via retrospective chart review of research visits that include neurologic exam, in-depth cognitive testing and magnetic resonance imaging (MRI) imaging. Forty one cases were included. Thirty two were diagnosed with FTD-MND, while nine cases were diagnosed as MND-only from clinical evaluation. Results: Ten FTLD-MND cases (31%) presented with prominent or isolated language involvement consistent with a diagnosis of primary progressive aphasia (PPA), which we called progressive aphasia with motor neuron disease (PA-MND). Of these, three cases that mirrored the non-fluent variant of PPA (nfvPPA) were named nfvPA-MND. The imaging pattern of these nfvPA-MND showed atrophy strictly confined to the frontal and anterior temporal language cortical areas. Another group of seven cases that resembled patients with the semantic variant PPA (svPPA) were named svPA-MND. The group of svPPA-MND on imaging analysis showed selective atrophy of the temporal lobe and orbitofrontal cortex. Conclusions: Language impairment was a frequent phenotype of FTD-MND associated with focal atrophy patterns within the language networks. This data suggest patients with FTD-MND can present quite often with language phenotype of nfvPPA and svPPA, as opposed to exclusive bvFTD symptoms.

Longitudinal Screening Detects Cognitive Stability and Behavioral Deterioration in ALS Patients.

Objective: To evaluate longitudinal cognitive/behavioral change over 12 months in participants enrolled in the ALS Multicenter Cohort Study of Oxidative Stress (ALS COSMOS). Methods: We analyzed data from 294 ALS participants, 134 of whom were studied serially. Change over time was evaluated controlling for age, sex, symptom duration, education, race, and ethnicity. Using multiple regression, we evaluated associations among decline in ALS Functional Rating Scale-Revised (ALSFRS-R) scores, forced vital capacity (FVC), and cognitive/behavioral changes. Change in cognitive/behavioral subgroups was assessed using one-way analyses of covariance. Results: Participants with follow-up data had fewer baseline behavior problems compared to patients without follow-up data. We found significant worsening of behavior (ALS Cognitive Behavioral Screen (ALS CBS) behavioral scale, p < 0.001; Frontal Behavioral Inventory-ALS (FBI-ALS) disinhibition subscale, p = 0.044). Item analysis suggested change in frustration tolerance, insight, mental rigidity, and interests (p < 0.05). Changes in ALSFRS-R correlated with the ALS CBS. Worsening disinhibition (FBI-ALS) did not correlate with ALSFRS-R, FVC, or disease duration. Conclusion: We did not detect cognitive change. Behavioral change was detected, and increased disinhibition was found among patients with abnormal baseline behavioral scores. Disinhibition changes did not correlate with disease duration or progression. Baseline behavioral problems were associated with advanced, rapidly progressive disease and study attrition.

Measurement of spinal cord atrophy using phase sensitive inversion recovery (PSIR) imaging in motor neuron disease.

BACKGROUND: The spectrum of motor neuron disease (MND) includes numerous phenotypes with various life expectancies. The degree of upper and lower motor neuron involvement can impact prognosis. Phase sensitive inversion recovery (PSIR) imaging has been shown to detect in vivo gray matter (GM) and white matter (WM) atrophy in the spinal cord of other patient populations but has not been explored in MND. METHODS: In this study, total cord, WM and GM areas of ten patients with a diagnosis within the MND spectrum were compared to those of ten healthy controls (HC). Patients' diagnosis included amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, primary muscular atrophy, facial onset sensory and motor neuronopathy and ALS-Frontotemporal dementia. Axial 2D PSIR images were acquired at four cervical disc levels (C2-C3, C3-C4, C5-C6 and C7-T1) with a short acquisition time (2 minutes) protocol. Total cross-sectional areas (TCA), GM and WM areas were measured using a combination of highly reliable manual and semi-automated methods. Cord areas in MND patients were compared with HC using linear regression analyses adjusted for age and sex. Correlation of WM and GM areas in MND patients was explored to gain insights into underlying atrophy patterns. RESULTS: MND patients as a group had significantly smaller cervical cord GM area compared to HC at all four levels (C2-C3: p = .009; C3-C4: p = .001; C5-C6: p = .006; C7-T1: p = .002). WM area at C5-C6 level was significantly smaller (p = .001). TCA was significantly smaller at C3-C4 (p = .018) and C5-C6 (p = .002). No significant GM and WM atrophy was detected in the two patients with predominantly bulbar phenotype. Concomitant GM and WM atrophy was detected in solely upper or lower motor neuron level phenotypes. There was a significant correlation between GM and WM areas at all four levels in this diverse population of MND. CONCLUSION: Spinal cord GM and WM atrophy can be detected in vivo in patients within the MND spectrum using a short acquisition time 2D PSIR imaging protocol. PSIR imaging shows promise as a method for quantifying spinal cord involvement and thus may be useful for diagnosis, prognosis and for monitoring disease progression.

Transcriptome analysis in whole blood reveals increased microbial diversity in schizophrenia.

The role of the human microbiome in health and disease is increasingly appreciated. We studied the composition of microbial communities present in blood across 192 individuals, including healthy controls and patients with three disorders affecting the brain: schizophrenia, amyotrophic lateral sclerosis, and bipolar disorder. By using high-quality unmapped RNA sequencing reads as candidate microbial reads, we performed profiling of microbial transcripts detected in whole blood. We were able to detect a wide range of bacterial and archaeal phyla in blood. Interestingly, we observed an increased microbial diversity in schizophrenia patients compared to the three other groups. We replicated this finding in an independent schizophrenia case-control cohort. This increased diversity is inversely correlated with estimated cell abundance of a subpopulation of CD8+ memory T cells in healthy controls, supporting a link between microbial products found in blood, immunity and schizophrenia.

Serious Bacterial Infections Acquired During Treatment of Patients Given a Diagnosis of Chronic Lyme Disease - United States.

The term "chronic Lyme disease" is used by some health care providers as a diagnosis for various constitutional, musculoskeletal, and neuropsychiatric symptoms (1,2). Patients with a diagnosis of chronic Lyme disease have been provided a wide range of medications as treatment, including long courses of intravenous (IV) antibiotics (3,4). Studies have not shown that such treatments lead to substantial long-term improvement for patients, and they can be harmful (1,5). This report describes cases of septic shock, osteomyelitis, Clostridium difficile colitis, and paraspinal abscess resulting from treatments for chronic Lyme disease. Patients, clinicians, and public health practitioners should be aware that treatments for chronic Lyme disease can carry serious risks.

Progression and effect of cognitive-behavioral changes in patients with amyotrophic lateral sclerosis.

BACKGROUND: To prospectively evaluate the progression of cognitive-behavioral function in amyotrophic lateral sclerosis (ALS) and examine the association of cognitive-behavioral deficits with disease progression, patient quality of life (QOL), and caregiver burden. METHODS: We evaluated cognitive-behavioral function using the Amyotrophic Lateral Sclerosis Cognitive Behavioral Screen at enrollment and after 7 months in a cohort of patients with ALS. Paired t tests were used to evaluate the change in the 2 assessments. Linear regression and Kruskal-Wallis tests were applied to investigate how initial cognitive or behavioral status related to outcomes. RESULTS: The mean test-retest interval was 6.8 months (SD 1.6). Cognitive status of the study population (n = 49) overall did not change over the study period (p = 0.06) despite progression of motor weakness (p < 0.001), though small subsets of the sample demonstrate cognitive change. Patients initially classified as behaviorally normal showed increased behavioral problems over time (t = -2.8, p = 0.009). Decline in cognitive (ß = -1.3, p = 0.03) and behavioral (ß = -0.76, p = 0.002) status predicted increasing caregiver burden. Behavioral abnormalities predicted decline in forced vital capacity and ALS Functional Rating Scale-Revised score (p = 0.008, 0.012) in the study population and patient QOL in the most severely affected group (t = 4.3, p = 0.003). CONCLUSIONS: Cognitive-behavioral change is a key aspect of disease heterogeneity in ALS. Executive function in ALS overall remains stable over 7 months as detected by an administered screening tool. However, patients may develop caregiver-reported behavioral symptoms in that time period. Screening for caregiver-reported symptoms has a particular utility in predicting future clinical decline, increased caregiver burden, and worsening patient QOL.

Cognitive-behavioral changes in amyotrophic lateral sclerosis: Screening prevalence and impact on patients and caregivers.

Our objective was to evaluate the association between cognitive-behavioral deficits and patient quality of life (QoL), caregiver burden, and disease stage in a population of patients with amyotrophic lateral sclerosis (ALS). We administered the ALS Cognitive-Behavioral Screen™ to 86 patients with ALS. Multiple regression was used to evaluate the association between cognitive or behavioral deficits and disease stage, patient QoL, and caregiver burden while controlling for clinically important variables. Of 86 participants enrolled, 53 (62%) had some degree of cognitive impairment, 32 (37%) were behaviorally impaired and four met both cognitive and behavioral screening criteria for frontotemporal dementia (FTD). The severity of cognitive-behavioral deficits was not associated with patient QoL. More pronounced cognitive deficits (beta = -1.4, p = 0.04) and behavioral symptoms (-0.69, p < 0.001) predicted higher caregiver burden. Self-reported QoL was lower in patients with more depressive symptoms (beta = -0.32, p < 0.001) and more advanced disease (beta =0.10, p = 0.01). In conclusion, general QoL for patients with ALS is not associated with cognitive or behavioral deficits. More severe cognitive deficits and caregiver-reported behavioral symptoms predict higher caregiver burden. Routine cognitive-behavioral screening can identify patients who require full neuropsychological examination, inform patient counseling, and identify caregivers in need of early, targeted interventions.

Primary Lateral Sclerosis and Early Upper Motor Neuron Disease: Characteristics of a Cross-Sectional Population.

OBJECTIVES: The goals of this study were to characterize clinical and electrophysiologic findings of subjects with upper motor neuron disease and to explore feasibility of clinical trials in this population. METHODS: Twenty northeast amyotrophic lateral sclerosis consortium (northeast amyotrophic lateral sclerosis) sites performed chart reviews to identify active clinical pure upper motor neuron disease patients. Patients with hereditary spastic paraplegia or meeting revised El Escorial electrodiagnostic criteria for amyotrophic lateral sclerosis were excluded. Patients were classified into 2 groups according to the presence or absence of minor electromyography (EMG) abnormalities. RESULTS: Two hundred thirty-three subjects with upper motor neuron disease were identified; 217 had available EMG data. Normal EMGs were seen in 140 subjects, and 77 had minor denervation. Mean disease duration was 84 (±80) months for the entire cohort with no difference seen between the 2 groups. No difference was seen in clinical symptoms, disability, or outcome measures between the 2 groups after correcting for multiple comparisons. CONCLUSIONS: Minor EMG abnormalities were not associated with phenotypic differences in a clinical upper motor neuron disease population. These findings suggest that subtle EMG abnormalities can not necessarily be used as a prognostic tool in patients with clinical upper motor neuron disease. This study also demonstrates the availability of a large number of patients with upper motor neuron diseases within the northeast amyotrophic lateral sclerosis network and suggests feasibility for conducting clinical trials in this population.

Cognitive-behavioral screening reveals prevalent impairment in a large multicenter ALS cohort.

OBJECTIVES: To characterize the prevalence of cognitive and behavioral symptoms using a cognitive/behavioral screening battery in a large prospective multicenter study of amyotrophic lateral sclerosis (ALS). METHODS: Two hundred seventy-four patients with ALS completed 2 validated cognitive screening tests and 2 validated behavioral interviews with accompanying caregivers. We examined the associations between cognitive and behavioral performance, demographic and clinical data, and C9orf72 mutation data. RESULTS: Based on the ALS Cognitive Behavioral Screen cognitive score, 6.5% of the sample scored below the cutoff score for frontotemporal lobar dementia, 54.2% scored in a range consistent with ALS with mild cognitive impairment, and 39.2% scored in the normal range. The ALS Cognitive Behavioral Screen behavioral subscale identified 16.5% of the sample scoring below the dementia cutoff score, with an additional 14.1% scoring in the ALS behavioral impairment range, and 69.4% scoring in the normal range. CONCLUSIONS: This investigation revealed high levels of cognitive and behavioral impairment in patients with ALS within 18 months of symptom onset, comparable to prior investigations. This investigation illustrates the successful use and scientific value of adding a cognitive-behavioral screening tool in studies of motor neuron diseases, to provide neurologists with an efficient method to measure these common deficits and to understand how they relate to key clinical variables, when extensive neuropsychological examinations are unavailable. These tools, developed specifically for patients with motor impairment, may be particularly useful in patient populations with multiple sclerosis and Parkinson disease, who are known to have comorbid cognitive decline.

Prospective study of cost of care at multidisciplinary ALS centers adhering to American Academy of Neurology (AAN) ALS practice parameters.

Multidisciplinary care in ALS is associated with longer survival, improved quality of life, and reduced hospital admissions, but there are no published data on institutional costs associated with multidisciplinary ALS care at U.S. centers. We prospectively examined institutional costs, adherence to AAN Practice Parameters and patient satisfaction in multidisciplinary ALS clinics at 18 U.S. ALS centers. Centers reported patient volumes; direct costs for staff salary/benefits, supplies and equipment; and institutional non-salary and overhead costs over a three-month period. In 1117 patients seen during this period, mean age was 61.5 years (range 25-91 years), 56% were male, and mean ALSFRS-R score was 29. Mean total salary/benefit cost per clinic day for all providers was $2964 (range $1692-$5236 across centers). Mean salary/benefit cost per patient per clinic was $507 (range $258-$806 across centers). Differences among centers in reporting non-salary costs prevented meaningful analysis. Practice parameter adherence and patient satisfaction were high. This prospective collaborative study demonstrates the direct financial burden of evidence-based multidisciplinary ALS care in the U.S.; more refined non-salary and overhead cost data are needed to evaluate the full cost impact of care. These data may be useful in supporting evidence-based models of patient centered care for ALS.