Gary Pattee

Mitochondria in Sporadic Amyotrophic Lateral Sclerosis

Mitochondria are abnormal in persons with amyotrophic lateral sclerosis (ALS) for unknown reasons. We explored whether aberration of mitochondrial DNA (mtDNA) could play a role in this by transferring mitochondrial DNA (mtDNA) from ALS subjects to mtDNA-depleted human neuroblastoma cells. Resulting ALS cytoplasmic hybrids (cybrids) exhibited abnormal electron transport chain functioning, increases in free radical scavenging enzyme activities, perturbed calcium homeostasis, and altered mitochondrial ultrastructure. Recapitulation of defects previously observed in ALS subjects and ALS transgenic mice by expression of ALS mtDNA support a pathophysiologic role for mtDNA mutation in some persons with this disease.

Bulbar and speech motor assessment in ALS: Challenges and future directions

Abstract Bulbar motor deterioration due to amyotrophic lateral sclerosis (ALS) leads to the eventual impairment of speech and swallowing functions. Despite these devastating consequences, no standardized diagnostic procedure for assessing bulbar dysfunction in ALS exists and adequate objective markers of bulbar deterioration have not been identified. In this paper, we consider objective measures of speech motor function, which show promise for forming the basis of a comprehensive, quantitative bulbar motor assessment in ALS. These measures are based on the assessment of four speech subsystems: respiratory, phonatory, articulatory, and resonatory. The goal of this research is to design a non-invasive, comprehensive bulbar motor assessment instrument intended for early detection, monitoring of disease progression, and clinical trial application. Preliminary data from an ongoing study of bulbar motor decline are presented, which demonstrate the potential clinical efficacy of the speech subsystem approach.

Acceptance of Augmentative and Alternative Communication Technology by Persons with Amyotrophic Lateral Sclerosis

A review of the use of augmentative and alternative communication (AAC) technology by 50 persons with amyotrophic lateral sclerosis was completed over the course of 4 years. Ninety-six percent of the participants in this study accepted AAC technology, either immediately (90%) or after some delay (6%), and only 4% (n = 2) rejected AAC technology. None of the participants discontinued use of their AAC technology. Reasons for acceptance decisions were discussed in interviews with study participants and the results are presented.

A protocol for identification of early bulbar signs in amyotrophic lateral sclerosis

The purpose of this project is to identify characteristics that may be of assistance in establishing the diagnosis and monitoring early progression of bulbar dysfunction in patients with Amyotrophic Lateral Sclerosis (ALS). Early identification of bulbar dysfunction would assist in clinical trials and management decisions. A database of 218 clinic visits of patients with ALS was developed and formed the basis for these analyses. As a framework for the description of our methodology, the Disablement Model [World Health Organization. WHO International classification of impairment, activity, and participation: beginners guide. In: WHO, editor. Beta-1 draft for field trials; 1999] was utilized. Our data identified that the strongest early predictors of bulbar speech dysfunction include altered voice quality (laryngeal control), speaking rate, and communication effectiveness. A protocol for measuring these speech parameters was therefore undertaken. This paper presents the protocol used to measure these bulbar parameters.

Kinematics of disease progression in bulbar ALS

UNLABELLED The goal of this study was to investigate the deterioration of lip and jaw movements during speech longitudinally in three individuals diagnosed with bulbar amyotrophic lateral sclerosis (ALS). The study was motivated by the need to understand the relationship between physiologic changes in speech movements and clinical measures of speech performance such as speaking rate and speech intelligibility. Movements of the lip and jaw were quantified with respect to their size speed, and duration. The data revealed several changes in lip and jaw movement that coincided with ALS progression. In two out of three speakers, the changes in measures of path distance and speed anticipated the drop in speech intelligibility by approximately 3 months. With disease progression, increases in movement duration coincided with declines in speech intelligibility. Overall, the movement measures appeared to be sensitive to disease progression in ALS. LEARNING OUTCOMES By the end of the manuscript, the reader should be able to: (1) describe the changes that occur in articulatory movements of the jaw and lower lip in ALS; (2) understand the relationship between physiologic measures of movement and speech intelligibility and speaking rate; (3) identify critical points in the disease progression and understand which quantitative measures reveal the state of the bulbar system at these time points.

Tongue Movements and Their Acoustic Consequences in Amyotrophic Lateral Sclerosis

Objective: The relations between acoustic measures and their articulatory bases have rarely been tested in dysarthria but are important for diagnostic and treatment purposes. We tested the association between acoustic measures of F2 range and F2 slope with kinematic measures of tongue movement displacement and speed in individuals with amyotrophic lateral sclerosis (ALS) and healthy controls speaking at normal and slow rates. Relations between acoustic and kinematic measures and speech intelligibility were examined. Results: As healthy controls reduced their speaking rate, their F2 slopes and movement speeds decreased. In talkers with ALS, acoustic and kinematic variables were associated with changes in speaking rate, characteristic of disease progression. Participants with slow rate had shallower F2 slopes and slower movement speeds than those with normal rate. Relations between F2 range and tongue displacement were weaker. F2 slope, displacement, and duration were correlated with speech intelligibility most consistently. Conclusion: Findings suggested that F2 slope is a useful marker for tracking disease progression in ALS. F2 slope reflects changes in tongue function with disease progression and is linked to speech intelligibility. Changes in movement speed, however, might be the earliest sign of disease in the tongue.

R(+) pramipexole as a mitochondrially focused neuroprotectant: Initial early phase studies in ALS

R(+) pramipexole (PPX) is a lipophilic cation that concentrates into brain and mitochondria and efficiently scavenges reactive oxygen and nitrogen species (RONS). Under the auspices of a Physician‐Sponsor IND, R(+)PPX was dosed to small numbers of ALS patients for tolerability and safety while efficacy measures were also collected. The purpose of this paper is to describe the outcomes of these initial clinical studies. In a futility design study, 30 patients with early SALS were evaluated monthly for ALSFRS‐R scores and FVC measurements for three months during lead‐in, followed by open‐label dosing at 30 mg/day of R(+)PPX for the next six months. In the dose escalation study, 10 subjects with early ALS received daily doses of R(+)PPX from 10 mg t.i.d. to 100 mg t.i.d. over seven weeks. In the open‐label extension analysis, subjects from the initial studies were treated with 30 mg/day for at least six months, then switched to 60 mg/day. R(+)PPX was tolerated well in all studies. In the futility study, slopes of decline in ALSFRS‐R scores and neurophysiological index (NI) values yielded non‐significant reductions during treatment. In the dose‐escalation study, all subjects increased daily R(+)PPX intake safely to 100 mg t.i.d. Markers of ALS did not change (ALSFRS‐R) or improved (FVC). Trough and peak plasma (PPX) increased linearly with dosing, and several subjects achieved plasma (PPX) >1 µM. In the open‐label extension protocol, changing from 30 to 60 mg/day caused a non‐significant 17% reduction in slope of decline of ALSFRS‐R. It was concluded that R(+)PPX was tolerated well in long‐term dosing at 30 and 60 mg/day. Encouraging but non‐significant effects of R(+)PPX on ALS decline were observed. High doses of R(+)PPX were tolerated well and yielded neuroprotective plasma levels. These findings support longer‐term testing of higher R(+)PPX doses as a potential disease‐altering therapy for SALS.

Reduction of oxidative stress in amyotrophic lateral sclerosis following pramipexole treatment

Oxidative abnormalities have been identified both in familial amyotrophic lateral sclerosis (FALS) and the more prevalent sporadic ALS (SALS). Mitochondrial dysfunction and toxic free radicals may play a role in this disease process, although the exact pathogenesis of both forms of ALS remains unknown. 2,3‐DHBA is a hydroxylated salicylate byproduct that has been shown to be a reliable marker of increased free radical activity and is reliably assayed by HPLC. Following an oral salicylate load, we found elevated serum levels of 2, 3‐dihydroxybenzoic acid (2,3‐DHBA) and DHBA/salicylate in SALS subjects. Pramipexole has been shown to reduce oxidative stress and be neuroprotective in cell and animal models of neurodegeneration. We studied 12 SALS patients to determine the levels of 2,3‐DHBA both before and after treatment with pramipexole. We found that pramipexole treatment up to 6 mg/day was well tolerated. The mean 2,3‐DHBA serum levels were reduced by 45% and DHBA/salicylate ratios declined by 59% following treatment with pramipexole. SALS patients show apparent increases in systemic oxygen radical production that are reduced by pramipexole treatment at conventional doses, suggesting that pramipexole or related compounds may interrupt free radical production in SALS.

Role of mitochondria in amyotrophic lateral sclerosis.

Neurodegeneration in amyotrophic lateral sclerosis (ALS) is characterized by the specific loss of central and peripheral motor neurons. While this pattern of neuronal demise gives rise to a distinct clinical syndrome, at the molecular level ALS pathology is similar to that seen in other neurodegenerative diseases. In particular, mitochondrial dysfunction in ALS is reminiscent of that observed in Alzheimers and Parkinsons diseases. Mitochondria in persons with ALS demonstrate impaired electron transport, increased free radical generation, and an inability to adequately buffer cellular and cytosolic calcium shifts. These abnormalities are probably systemic and potentially due to mutation of mitochondrial DNA. (ALS 2000; 1:185-190)

A novel fixed-target task to determine articulatory speed constraints in persons with amyotrophic lateral sclerosis.

PURPOSE The goal of this study was to determine if talkers with ALS are limited in their ability to increase lower lip and jaw speed at an early stage of the disease when their speaking rate and intelligibility are only minimally or not affected. METHOD A novel metronome paced fixed-target task was used to assess movement speed capacities during lower lip and jaw oscillations in seven talkers with ALS and seven age and gender matched controls. RESULTS Lower lip peak speeds were significantly lower in talkers with mild ALS than in healthy talkers suggesting a lower lip speed constraint in talkers with mild ALS. Jaw peak speeds tended to be lower, but jaw displacements tended to be larger in talkers with mild ALS than in healthy talkers. Because greater speeds are typically expected for larger displacements, outcomes also suggest a jaw speed constraint in talkers with mild ALS. CONCLUSIONS Lower lip and jaw peak speeds may be sensitive measures to identify bulbar motor performance decline at an early stage of the disease when speaking rate and intelligibility are only minimally affected. LEARNING OUTCOMES The reader will be able to explain two different articulatory strategies to increase speaking rate and understand why fast speech tasks and diadochokinetic pseudo-speech tasks are not suited to assess articulatory speed capacity in healthy and impaired talkers. The reader will also be able to explain how orofacial movement speed capacity can be tested using a fixed-target task and how ALS affects lower lip and jaw speed capacities during the early stages of the disease.