Regional prefrontal cortical atrophy predicts specific cognitive-behavioral symptoms in ALS-FTD.

Amyotrophic Lateral Sclerosis-Frontotemporal Dementia (ALS-FTD) may present typical behavioral variant FTD symptoms. This study aims to determine whether profile and severity of cognitive-behavioral symptoms in ALS/ALS-FTD are predicted by regional cortical atrophy. The hypothesis is that executive dysfunction can be predicted by dorsolateral prefrontal cortical (dlPFC) atrophy, apathy by dorsomedial PFC (dmPFC) and anterior cingulate cortical (ACC) atrophy, disinhibition by orbitofrontal cortical (OFC) atrophy. 3.0 Tesla MRI scans were acquired from 22 people with ALS or ALS-FTD. Quantitative cortical thickness analysis was performed with FreeSurfer. A priori-defined regions of interest (ROI) were used to measure cortical thickness in each participant and calculate magnitude of atrophy in comparison to 115 healthy controls. Spearman correlations were used to evaluate associations between frontal ROI cortical thickness and cognitive-behavioral symptoms, measured by Neuropsychiatric Inventory Questionnaire (NPI-Q) and Clinical Dementia Rating (CDR) scale. ALS-FTD participants exhibited variable degrees of apathy (NPI-Q/apathy: 1.6 ± 1.2), disinhibition (NPI-Q/disinhibition: 1.2 ± 1.2), executive dysfunction (CDR/judgment-problem solving: 1.7 ± 0.8). Within the ALS-FTD group, executive dysfunction correlated with dlPFC atrophy (ρ:-0.65;p < 0.05); similar trends were seen for apathy with ACC (ρ:-0.53;p < 0.10) and dmPFC (ρ:-0.47;p < 0.10) atrophy, for disinhibition with OFC atrophy (ρ:-0.51;p < 0.10). Compared to people with ALS, those with ALS-FTD showed more diffuse atrophy involving precentral gyrus, prefrontal, temporal regions. Profile and severity of cognitive-behavioral symptoms in ALS-FTD are predicted by regional prefrontal atrophy. These findings are consistent with established brain-behavior models and support the role of quantitative MRI in diagnosis, management, counseling, monitoring and prognostication for a neurodegenerative disorder with diverse phenotypes.

Improving symptom management for people with amyotrophic lateral sclerosis.

INTRODUCTION: Symptomatic management is the main focus of ALS clinical care. We aim to report the prevalence of ALS-related symptoms and characterize self-reported symptomatic management. METHODS: A symptom management survey developed by the Muscular Dystrophy Association Clinical Research Network was completed by ALS registrants. Logistic regression identified potential predictors of symptom prevalence, severity, and treatment. RESULTS: A total of 567 ALS participants reported fatigue (90%), muscle stiffness (84%), and muscle cramps (74%) as most prevalent symptoms. Fatigue (18%), muscle stiffness (14%), and shortness of breath (12%) were most bothersome. Although fatigue was the most prevalent symptom, it was also least treated (10%). Neither location of care nor disease duration was associated with symptom prevalence, severity, or probability of receiving treatment. DISCUSSION: This large patient-reported symptom survey suggests that fatigue is the most prevalent, bothersome, and undertreated ALS symptom. Improving ALS symptom management is an unmet medical need and clinical trials of symptomatic treatments are needed. Muscle Nerve 57: 20-24, 2018.

Analysis of Participant Withdrawal in Huntington Disease Clinical Trials.

BACKGROUND: Excellent retention in Huntington disease (HD) clinical trials is essential for testing new therapies. The stage of disease, cognitive status, and availability of a care partner may influence retention in HD clinical trials. OBJECTIVE: We sought to analyze reasons for early withdrawal in three HD clinical trials, and evaluated if either baseline characteristics or follow-up assessments were associated with time to withdrawal. METHODS: Analyses of participant withdrawal were performed for three randomized, double-blind, placebo-controlled trials including the CARE-HD (coenzyme Q10 and remacemide in HD, n = 347), DOMINO (pilot study of minocycline in HD, n = 114), and 2CARE (coenzyme Q10 in HD, n = 609) trials. Reasons for withdrawal were obtained by review of textual data in the study databases. Participant demographic and clinical characteristics were analyzed as potential predictors of time to withdrawal using Cox-proportional hazards models. RESULTS: Estimated probabilities of withdrawal at 12 months were 2.9% for CARE-HD, 10.5% for DOMINO, and 5.9% for 2CARE. The top reasons for withdrawal (202 in total), expressed as mean percentage across the three trials, were loss to follow-up (23.2%), death (15.9%), and loss of interest/desire to participate (15.2%). Baseline and time-dependent variables associated with time to withdrawal were mainly motor, behavioral, and functional scores. Age, gender, ethnicity, and educational level were not associated with time to withdrawal in any of the three studies. CONCLUSIONS: The estimated withdrawal probability at 12 months ranged from 2.9% to 10.5% in the three HD trials considered here. A possible strategy to improve retention of participants in future HD clinical trials is to enroll individuals with higher baseline functional and behavioral status.

Ultra high-field (7tesla) magnetic resonance spectroscopy in Amyotrophic Lateral Sclerosis.

The main objective of this study was to utilize high field (7T) in vivo proton magnetic resonance imaging to increase the ability to detect metabolite changes in people with ALS, specifically, to quantify levels of glutamine and glutamine separately. The second objective of this study was to correlate metabolic markers with clinical outcomes of disease progression. 13 ALS participants and 12 age-matched healthy controls (HC) underwent 7 Tesla MRI and MRS. Single voxel MR spectra were acquired from the left precentral gyrus using a very short echo time (TE = 5 ms) STEAM sequence. MRS data was quantified using LCModel and correlated to clinical outcome markers. N-acetylaspartate (NAA) and total NAA (tNA, NAA + NAAG) were decreased by 17% in people with ALS compared to HC (P = 0.004 and P = 0.005, respectively) indicating neuronal injury and/or loss in the precentral gyrus. tNA correlated with disease progression as measured by forced vital capacity (FVC) (P = 0.014; Rρ = 0.66) and tNA/tCr correlated with overall functional decline as measured by worsening of the ALS Functional Rating Scale-Revised (ALSFRS-R) (P = 0.004; Rρ = -0.74). These findings underscore the importance of NAA as a reliable biomarker for neuronal injury and disease progression in ALS. Glutamate (Glu) was 15% decreased in people with ALS compared to HC (P = 0.02) while glutamine (Gln) concentrations were similar between the two groups. Furthermore, the decrease in Glu correlated with the decrease in FVC (P = 0.013; Rρ = 0.66), a clinical marker of disease progression. The decrease in Glu is most likely driven by intracellular Glu loss due to neuronal loss and degeneration. Neither choline containing components (Cho), a marker for cell membrane turnover, nor myo-Inositol (mI), a suspected marker for neuroinflammation, showed significant differences between the two groups. However, mI/tNA was correlated with upper motor neuron burden (P = 0.004, Rρ = 0.74), which may reflect a relative increase of activated microglia around motor neurons. In summary, 7T 1H MRS is a powerful non-invasive imaging technique to study molecular changes related to neuronal injury and/or loss in people with ALS.

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.

Diagnostic timelines and delays in diagnosing amyotrophic lateral sclerosis (ALS).

The objective of this study was to characterize the diagnostic timelines and their predictors in people with amyotrophic lateral sclerosis (ALS). Patients were identified through ALS billing codes. Time from presenting symptom to first doctor visit, first doctor visit to suspected ALS diagnosis, suspected to confirmed ALS diagnosis, and presenting symptom to confirmed ALS diagnosis (total diagnostic time) were collected. Regression models were used to analyze the predictors of diagnostic delay. Three hundred and four ALS patients were included in the analysis. Median total diagnostic time was 11.5 months. Diagnostic timelines were longer in patients with age > 60 years (p < 0.001), sporadic ALS (p = 0.043), and limb onset (p = 0.010). The presence of fasciculations, slurred speech, and lower extremity weakness when symptoms were first noted were independent predictors of shorter time to ALS diagnosis (p = 0.04, p = 0.02, and p = 0.04, respectively). About half of the patients (52%) received an alternative diagnosis and each patient saw an average of three different physicians before ALS diagnosis was confirmed. In conclusion, diagnostic timelines in ALS are long, and patients see many physicians and receive multiple alternative diagnoses before the diagnosis of ALS is confirmed. Older age, sporadic disease, and limb onset can delay ALS diagnosis.