The role of the corticomotorneurons in pathogenesis of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive, degenerative disease of the motor system clinically defined by the presence of upper and lower motor neuron (LMN) signs. The site of onset of pathophysiology within the motor system in ALS remains unresolved and this thesis examines the role of the corticomotor neuron in the pathogenesis of ALS. The diagnostic utility of the split-hand sign in ALS involving preferential wasting of the ‘thenar’ group of intrinsic hand muscles namely the abductor pollicis brevis (APB) and first dorsal interosseous (FDI) was established by recording the split-hand index (SI) which was noted to reliably differentiate ALS from mimic neuromuscular disorders. The cortical and axonal excitability characteristics of the ‘thenar’ muscles namely the APB and FDI was compared with the hypothenar abductor digiti minimi (ADM) with threshold tracking transcranial magnetic stimulation (TMS) studies revealing cortical hyperexcitability to be a feature of ALS pronounced over the ‘thenar’ muscles while axonal hyperexcitability while a feature of ALS, did not selectively affect the prominently wasted ‘thenar’ muscles. Cortical hyperexcitability was also noted to precede the development of lower motor neuron dysfunction in a clinically and neurophysiologically normal APB muscle. The selective vulnerability of muscles in ALS was further defined by the split hand plus sign with a greater degree of cortical hyperexcitability over the preferentially wasted APB muscle in ALS patients when compared with a similarly innervated and relatively preserved flexor pollicis longus (FPL) muscle. In summary, corticomotorneuronal hyperexcitability as a marker of corticomotorneuronal dysfunction predominates over the muscles which are preferentially wasted in ALS and precedes evidence of lower motor neuron loss. The findings presented in this thesis support the primacy of the corticomotor neuron in the pathogenesis of the split hand phenomenon and suggest a mechanism for the pathogenesis of ALS

The role of the corticomotorneurons in pathogenesis of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive, degenerative disease of the motor system clinically defined by the presence of upper and lower motor neuron (LMN) signs. The site of onset of pathophysiology within the motor system in ALS remains unresolved and this thesis examines the role of the corticomotor neuron in the pathogenesis of ALS. The diagnostic utility of the split-hand sign in ALS involving preferential wasting of the ‘thenar’ group of intrinsic hand muscles namely the abductor pollicis brevis (APB) and first dorsal interosseous (FDI) was established by recording the split-hand index (SI) which was noted to reliably differentiate ALS from mimic neuromuscular disorders. The cortical and axonal excitability characteristics of the ‘thenar’ muscles namely the APB and FDI was compared with the hypothenar abductor digiti minimi (ADM) with threshold tracking transcranial magnetic stimulation (TMS) studies revealing cortical hyperexcitability to be a feature of ALS pronounced over the ‘thenar’ muscles while axonal hyperexcitability while a feature of ALS, did not selectively affect the prominently wasted ‘thenar’ muscles. Cortical hyperexcitability was also noted to precede the development of lower motor neuron dysfunction in a clinically and neurophysiologically normal APB muscle. The selective vulnerability of muscles in ALS was further defined by the split hand plus sign with a greater degree of cortical hyperexcitability over the preferentially wasted APB muscle in ALS patients when compared with a similarly innervated and relatively preserved flexor pollicis longus (FPL) muscle. In summary, corticomotorneuronal hyperexcitability as a marker of corticomotorneuronal dysfunction predominates over the muscles which are preferentially wasted in ALS and precedes evidence of lower motor neuron loss. The findings presented in this thesis support the primacy of the corticomotor neuron in the pathogenesis of the split hand phenomenon and suggest a mechanism for the pathogenesis of ALS

Cortical hyperexcitability in Amyotrophic Lateral Sclerosis: Diagnostic and pathophysiological biomarker

Amyotrophic lateral sclerosis (ALS) is a progressive and degenerative disease of the motor system clinically defined by the presence of upper and lower motor neuron (UMN/LMN) signs. In this thesis the current diagnostic criteria were evaluated, both with a meta-analytical approach and a prospective multicenter design. The lack of an objective UMN biomarker resulted in a delayed diagnosis. Hence a novel threshold tracking transcranial magnetic stimulation (TMS) technique was utilised to measure cortical hyperexcitability, as a biomarker of UMN dysfunction. Cortical hyperexcitability facilitated an earlier diagnosis. This technique was then utilised to gain insights in familial ALS (c9orf72 repeat expansion). Cortical and peripheral nerve abnormalities were evident in familial ALS, but asymptomatic carriers had no evidence of cortical or peripheral nerve dysfunction. We then studied atypical ALS phenotypes such as the clinically UMN predominant variant, primary lateral sclerosis (PLS), reliably differentiating PLS from mimic disorders such as hereditary spastic paraparesis (HSP). In the lower motor neuron variant of ALS, termed flail leg syndrome, cortical hyperexcitability was only evident in patients with upper motor neuron signs. Taken together, these findings suggest that cortical hyperexcitability is a potentially robust diagnostic and pathophysiological biomarker in sporadic, familial and some atypical ALS variants

Contribution of Dysferlin-Containing Membranes to Membrane Repair in Skeletal Muscle.

The ability to repair the sarcolemma following injury is critical for muscle cells, and impaired membrane repair capacity is associated with inherited muscular dystrophy. Dysferlin is a membrane protein hypothesized to contribute to membrane repair by regulating vesicle-vesicle or vesicle-sarcolemma fusion, but the mechanism by which different dysferlin-containing membrane compartments contribute to membrane repair in skeletal muscle is unknown. While interactions between vesicles and the cytoskeleton may be involved in membrane resealing in non-muscle cells, whether interactions between dysferlin-containing membranes and the cytoskeleton are required for sarcolemma repair in muscle is unknown. Therefore, the goal of this thesis was to examine the mechanism by which dysferlin-containing compartments contribute to membrane repair in myotubes and adult muscle fibers, and test the overall hypothesis that dynamic interactions between dysferlin-containing membranes and the cytoskeleton are critical for membrane resealing in skeletal muscle. Live-cell imaging of dysferlin-eGFP expressing myotubes or dysferlin-pHGFP expressing myofibers isolated from a novel transgenic reporter mouse were used to explore the dynamic behavior of dysferlin-containing membranes at rest and during membrane repair. Dysferlin localizes primarily to intracellular vesicles that interact directly with microtubules in developing myotubes, but is restricted largely to the plasma membrane and t-tubules in mature adult skeletal muscle fibers. Mechanical wounding of myotubes induces rapid microtubule-dependent vesicle-vesicle fusion to form large dysferlin-containing vesicles which may plug large lesions. Interestingly, sarcolemma wounding in adult fibers induces formation of large vesicles by endocytosis, but more prominently rapid actin-dependent recruitment of sarcolemma-derived dysferlin to wounds. Dysferlin recruitment results in the formation of stable dysferlin-rich regions surrounding the lesion, and is required for membrane resealing, potentially by concentrating the lipid-binding function of dysferlin specifically at lesions. In summary, this thesis work shows that dysferlin localizes to specific damage-responsive membrane compartments in muscle, and demonstrates that interactions between dysferlin-containing membranes and the intracellular cytoskeleton is essential for dysferlin function in membrane repair. The transgenic reporter mouse described here will also be a valuable tool for future studies into the mechanisms of dysferlin-mediated membrane repair in normal muscle injury and inherited muscle diseases.PhDMolecular and Integrative PhysiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/107135/1/jmcdade_1.pd