Jonathan Hupf

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.

Depression and wish to die in a multicenter cohort of ALS patients.

Abstract Our objective was to determine prevalence of depressive disorders and wish to die at the baseline visit of a longitudinal multisite study of patients with ALS. Structured telephone interviews were conducted with patients diagnosed in past 18 months at 16 U.S. ALS centers. Demographic, medical, psychiatric and other psychological measures were administered. Of 329 patients assessed, mean ALSFRS-R score was 36.6; 88% (289/329) had no depressive disorder, 7% (24/329) had minor depression, and 5% (16/329) had current major depressive disorder (DSM-IV criteria). Demographic, financial and employment factors were unrelated to depression, as were duration of ALS symptoms and respiratory status, although depressed patients had lower scores on the total ALSFRS-R (p = 0.004) and gross motor function (p < 0.001). Depressed patients reported less pleasure, greater suffering, weariness and anxiety, more stress, were less hopeful, felt less control over illness management, reported lower quality of life, more often had thoughts about ending their lives and hastening death (all p < 0.001). Of the 62 patients (19% of the sample) who expressed a wish to die, only 37% (23/62) were clinically depressed. In conclusion, depressive disorders are not necessarily to be expected of ALS patients. Wish to die is not always expressed in the context of depression and does not necessarily represent psychopathology as such.

Japanese and American ALS patient preferences regarding TIV (tracheostomy with invasive ventilation): A cross-national survey

Abstract Substantial disparities in TIV utilization rates among ALS patients have been observed, with rates in Japan far exceeding rates in the United States. Our objective was to elicit national preferences and their determinants. We predicted more Japanese than American patients would desire TIV, as would sicker patients, those already using non-invasive interventions, and those with more positive mood and outlook. Patients were enrolled in five U.S. states and six Japanese regions. Eligible patients completed surveys during clinic visits (U.S.) or at home (Japan). Survey responses were in multiple-choice format and took about 15 min to complete. One hundred and fifty-six Americans and 66 Japanese patients participated. Contrary to expectations, Japanese patients were more likely to oppose TIV, as were those on 24-h NIV and patients who knew someone using TIV. Most Japanese and American patients with advanced respiratory impairment were undecided or opposed to TIV, while nearly 20% in both countries were in favor. Finally, patients who favored TIV or who were undecided had more energy, greater wish to live, and more sense of control over ALS management. In conclusion, factors other than patient preferences, such as neurologist preferences, caregiver attitudes and perhaps lack of advance planning, may influence probability of TIV utilization.

Phenotypic and molecular analyses of primary lateral sclerosis

Objective: To understand phenotypic and molecular characteristics of patients with clinically “definite” primary lateral sclerosis (PLS) in a prospective study. Methods: Six sites enrolled 41 patients who had pure upper motor neuron dysfunction, bulbar symptoms, a normal EMG done within 12 months of enrollment, and onset of symptoms ≥5 years before enrollment. For phenotypic analyses, 27 demographic, clinical, and cognitive variables were analyzed using the k-means clustering method. For molecular studies, 34 available DNA samples were tested for the C9ORF72 mutation, and exome sequencing was performed to exclude other neurologic diseases with known genetic cause. Results: K-means clustering using the 25 patients with complete datasets suggested that patients with PLS can be classified into 2 groups based on clinical variables, namely dysphagia, objective bulbar signs, and urinary urgency. Secondary analyses performed in all 41 patients and including only variables with complete data corroborated the results from the primary analysis. We found no evidence that neurocognitive variables are important in classifying patients with PLS. Molecular studies identified C9ORF72 expansion in one patient. Well-characterized pathogenic mutations were identified in SPG7, DCTN1, and PARK2. Most cases showed no known relevant mutations. Conclusions: Cluster analyses based on clinical variables indicated at least 2 subgroups of clinically definite PLS. Molecular analyses further identified 4 cases with mutations associated with amyotrophic lateral sclerosis, Parkinson disease, and possibly hereditary spastic paraplegia. Phenotypic and molecular characterization is the first step in investigating biological clues toward the definition of PLS. Further studies with larger numbers of patients are essential.

ALS Multicenter Cohort Study of Oxidative Stress (ALS COSMOS): Study methodology, recruitment, and baseline demographic and disease characteristics

Abstract In a multicenter study of newly diagnosed ALS patients without a reported family history of ALS, we are prospectively investigating whether markers of oxidative stress (OS) are associated with disease progression. Methods utilize an extensive structured telephone interview ascertaining environmental, lifestyle, dietary and psychological risk factors associated with OS. Detailed assessments were performed at baseline and at 3–6 month intervals during the ensuing 30 months. Our biorepository includes DNA, plasma, urine, and skin. Three hundred and fifty-five patients were recruited. Subjects were enrolled over a 36-month period at 16 sites. To meet the target number of subjects, the recruitment period was prolonged and additional sites were included. Results showed that demographic and disease characteristics were similar between 477 eligible/non-enrolled and enrolled patients, the only difference being type of health insurance among enrolled patients. Sites were divided into three groups by the number of enrolled subjects. Comparing these three groups, the Columbia site had fewer ‘definite ALS’ diagnoses. This is the first prospective, interdisciplinary, in-depth, multicenter epidemiological investigation of OS related to ALS progression and has been accomplished by an aggressive recruitment process. The baseline demographic and disease features of the study sample are now fully characterized.

Non-invasive measurement of abnormal ventilatory mechanics in amyotrophic lateral sclerosis

In this study we investigated non‐invasive, effort‐independent measurement of ventilatory mechanics in patients with amyotrophic lateral sclerosis (ALS).

Telephone based cognitive-behavioral screening for frontotemporal changes in patients with amyotrophic lateral sclerosis (ALS)

Abstract Our objective was to establish a valid and reliable battery of measures to evaluate frontotemporal dementia (FTD) in patients with ALS over the telephone. Thirty-one subjects were administered either in-person or by telephone-based screening followed by the opposite mode of testing two weeks later, using a modified version of the UCSF Cognitive Screening Battery. Equivalence testing was performed for in-person and telephone based tests. The standard ALS Cognitive Behavioral Screen (ALS-CBS) showed statistical equivalence at the 5% significance level compared to a revised phone version of the ALS-CBS. In addition, the Controlled Oral Word Association Test (COWAT) and Center for Neurologic Study-Lability Scale (CNS-LS) were also found to be equivalent at the 5% and 10% significance level, respectively. Similarly, the Mini-Mental State Examination (MMSE) and the well-established Telephone Interview for Cognitive Status (TICS) were also statistically equivalent. Equivalence could not be claimed for the ALS-Frontal Behavioral Inventory (ALS-FBI) caregiver interview and the Written Verbal Fluency Index (WVFI). In conclusion, our study suggests that telephone-based versions of the ALS-CBS, COWAT, and CNS-LS may offer clinicians valid tools to detect frontotemporal changes in the ALS population. Development of telephone based cognitive testing for ALS could become an integral resource for population based research in the future.