MULTIPLE SYSTEM ATROPHY

By Douglas F. Watt, Ph.D.

Adjunct Professor, Graduate Department of Psychology Lesley University

Clinical Neuroscience Advisor, 9th Dimension Biotech, Inc.

Multiple system atrophy is a tripartite disease, a similar ‘meta-category’ to the more recent integration of the frontotemporal dementias with ALS, but achieved some 40 years earlier, in which seemingly unrelated clinical phenotypes are shown to share identical cellular neuropathology. MSA is the diagnostic umbrella label, a ‘super-category’ emerging from Graham & Oppenheimer’s (1969) unification of three previously distinct syndromes: olivopontocerebellar atrophy, striatonigral degeneration, and Shy-Drager syndrome. This phenotypic integration was supported by pathological demonstration of pathognomonic glial (oligodendrocyte) cytoplasmic inclusions (GCIs) in all MSA by Papp in 1989. GCIs are composed of a unique strain of alpha synuclein aggregates, similar but not identical to strains in neurons in Parkinson's disease (‘Lewy bodies’), with seeding/templating of protein aggregation in a prion-like fashion. What makes multiple system atrophy something of an outlier in the already confusing pantheon of neurodegenerative disorders are: 1) GCIs are non-neuronal – MSA is an ‘oligodendropathy’ in which the cells supporting the brain's white matter degenerate, with neuronal degeneration apparently secondary to this; 2) there is no known genetic version of the disease (virtually all sporadic), in stark contrast to every other known neurodegenerative disorder, and where its closest relative PD has several genetically determined as well as genetically predisposed phenotypes, although copy number variations on SYNC have been found; 3) despite its close similarity to the PD family, with both a parkinsonian version that is roughly as commonplace as the cerebellar variant, and with a synucleinopathy somewhat similar to PD, it does not respond very well to levodopa, probably because the target system (putamen initially, then caudate) is degenerating more than in PD, while both show degeneration in SNc. In that sense, MSA is a more complex/diffuse disorder of neural networks, while PD (at least early-stage) may be viably (if incompletely) modeled as DA deafferentation. MSA is also more significantly aggressive than PD.

DA therapies may be modestly effective about 35-40% of the time, and may be worth trying with the parkinsonian variant, but often times autonomic dysfunction, and progressive cerebellar dysfunction pose greater challenges for patient quality of life, with cerebellar ataxia currently untreatable, other than removing risk for falls by walker or wheelchair support. Major questions remain about how degeneration initiates and apparently centers in the oligodendrocytes, and how to readily identify and then modify this neurodegenerative trajectory. Unfortunately, the lack of biomarkers makes identification of prodromal and preclinical stage patients difficult, particularly given lack of knowledge about risk genes, which significantly hampers research. OM-αSynD (detection of alpha synuclein in olfactory mucosa) may serve as a novel non-invasive biomarker for clinical diagnoses of PD, MSA-P, and MSA-C, but cannot yet discriminate these three, but skin biopsy may do better. Clinical stage patients can be neuroimaged, which has characteristic findings in both parkinsonian and cerebellar versions, about the only cost-effective biomarker and technical assist in differential diagnosis, beyond delineating symptom clusters and identifying classic ‘red flags’ that separate MSA & other Parkinsonian Plus disorders from PD. An experimental PET ligand has shown promise separating MSA from PD, but with no current clinical availability. DTI can separate PD & MSA, due to greater white matter degeneration in MSA.  

Classic disease modification targets in MSA (targeted in other NDD) have included: 1) antibodies aimed at alpha synuclein (all phase I), 2) inhibition of protein aggregation, 3) modulating central inflammation, and 4) augmenting growth factor/neuroprotection signals. So far, although no major disease modifying therapy has emerged, high-dose CoQ10 shows modest slowing of progression, suggesting that MITO dysfunction is part of the neurodegenerative causal loops (primacy of MITO dysfunction thought central to PD). Mesenchymal stem cell treatment also modestly slows progression. Only rapamycin has had any kind of probing in terms of clinical trials using CR mimetics (not successful in its one trial); this suggests a wide-open field of clinical opportunity for other CRMs, such as AMP kinase modulators, or perhaps combination approaches using a CRM and other classic targets from the above list. Virtually nothing is known in a systematic way about prevention and the relationship of MSA risk to classic disease-of-aging-relevant lifestyle risk factors of sleep, diet, exercise, or social support/stress, but attention to these classic risk factors may take gas off the neurodegenerative fire.