Determining the impact of specialized care on health outcomes and health care utilization in Parkinsonism.

BACKGROUND: Although care of Parkinsonism (PKM) is assumed to be optimally provided by movement disorder neurologists within an interdisciplinary clinic model, there is a paucity of published data to support this. OBJECTIVES: To investigate the impact of movement disorder neurologist care of individuals with Parkinsonism (PKM). METHODS: A retrospective exposure design was adopted using administrative data. Incident PKM individuals were identified in billing claims. A nine-year exposure period to movement disorder neurologist, general neurologist and non-neurologist care was calculated based on the billing codes. Regression models were used to test the association of provider exposure on time to death and long-term care (LTC) admission. Linear models were used to test varying provider exposure and hospital admissions, hospital days and emergency department visits. RESULTS: 1914 incident individuals were identified. There was no difference in PKM mortality, emergency visits, hospital admissions, or hospital days between providers, however exposure to general neurology and non-neurology care was associated with a significantly higher risk of admission to LTC compared to movement disorder neurologist care (HR 1.43; 95% CI 1.09-1.87 for general neurology (p-value = 0.0089); HR 1.61; 95% CI 1.25-2.05 for non-neurology (p-value = 0.0002), respectively. CONCLUSION: Movement disorder neurologist care is associated with a lower risk of admission to LTC over general neurologist care in individuals with PKM.

Mitofusin 2 Variant Presenting With a Phenotype of Multiple System Atrophy of Cerebellar Subtype.

Objectives: To investigate the etiology of cerebellar ataxia in an adult male patient. Methods: We performed standard neurologic assessment and genome sequencing of a 62-year-old man with rapidly progressive balance and gait abnormalities. Results: The propositus exhibited cognitive dysfunction, mild appendicular bradykinesia, prominent appendicular ataxia, dysarthria, and hypomimia with minimal dysautonomic symptoms. Nerve conduction studies showed mild peripheral sensory neuropathy and normal motor nerve conduction velocities. Brain imaging showed progressive cerebellar atrophy and gliosis of the olivopontocerebellar fibers, characterized by T2 hyperintensity within the pons. Genetic testing revealed a likely pathogenic germline variant in MFN2 (NM_014874: c.[838C>T];[=], p.(R280C)) in the GTPase domain (G) interface; pathogenic variants of MFN2 typically cause hereditary sensory and motor neuropathy VI or Charcot-Marie-Tooth disease 2A. The presence of progressive ataxia, "hot cross bun" sign, and dysautonomia has been associated with multiple system atrophy, cerebellar type (MSA-C). Discussion: We describe progressive cerebellar ataxia in an individual with a deleterious variant in MFN2. Our findings suggest that pathogenic variants in MFN2 can result in a spectrum of phenotypes including cerebellar ataxia with cerebellar-pontine atrophy in the absence of significant neuropathy and in a manner closely resembling MSA-C.

Calcineurin inhibition enhances motor neuron survival following injury.

The immunosuppressive agents cyclosporin A (CsA) and FK-506 have previously been shown to exhibit neurotrophic and neuroprotective properties in vivo. Given that significant clinical expertise exists for both drugs, they represent an attractive starting point for treatment of acute neural injuries. One putative mechanism for neuroprotection by these drugs relates to inhibition of calcineurin activity. However each drug-immunophilin complex can potentially influence additional signal transduction pathways. Furthermore, several non-immunosuppressive immunophilin ligands have been described as possessing neuroprotective properties, suggesting that neuroprotection may be separable from calcineurin inhibition. In the present study, we examined the mechanism of this neuroprotection in facial motor neurons following axotomy-induced injury. Similar to previous studies in rats, CsA and FK-506 enhanced motor neuron survival in mice following acute injury. To examine the mechanism responsible for neuroprotection by these agents, pharmacologic inhibitors of several potential alternate signalling pathways (17-(allylamino)-17-demethoxygeldanamycin, rapamycin, cypermethrin) were evaluated with respect to neuroprotection. Of these, only cypermethrin, a direct calcineurin inhibitor not previously associated with neuronal survival properties, was observed to significantly enhance motor neuron survival following injury. The results demonstrate for the first time that direct inhibition of calcineurin is neuroprotective in vivo. These data support a model in which calcineurin inhibition promotes neuronal survival, distinct from effects upon neurite outgrowth.

Inhibition of apoptosome activation protects injured motor neurons from cell death.

Within the mammalian central nervous system many forms of neurodegenerative injury are regulated via programmed cell death, a highly conserved program of cellular suicide. Programmed cell death is regulated by multiple signaling pathways, which have been identified within mammalian cells, although several lines of evidence suggest that the intrinsic pathway predominantly regulates the death of motor neurons following acute injury in vivo. We have tested this hypothesis by performing facial axotomies on cytochrome c knock-in mice containing a point mutation in the genomic locus of cytochrome c resulting in a lysine to alanine conversion at position 72 of the protein. The introduced mutation inhibits the ability of cytochrome c to induce the formation of the apoptosome, a protein complex that is principally required for the activation of the intrinsic pathway, but does not alter its function in oxidative phosphorylation. Homozygous cytochrome c knock-in mutants displayed a significant enhancement in motor neuron survival following injury when compared with littermate controls, thus establishing the apoptosome as a viable target for protecting motor neurons from neural injury. However, protection of facial motor neurons differs from that previously reported in mice either overexpressing anti-apoptotic or lacking pro-apoptotic members of the Bcl-2 family, which are thought to regulate several aspects of mitochondrial dysfunction including the release of cytochrome c from the mitochondria to the cytoplasm. Therefore, these results directly demonstrate for the first time the influence of the apoptosome on injury-induced neuronal programmed cell death in vivo isolated from upstream Bcl-2 family-mediated effects.

Designer drugs that are potent inhibitors of CYP2D6.

Some abused drugs are substrates of CYP2D6 (e.g., paramethoxyamphetamine, methylenedioxy-methamphetamine). CYP2D6 inhibition by concurrently used drugs of abuse could potentiate such drugs and increase acute toxicity. Ten designer drugs were tested as inhibitors of CYP2D6. Only 1-methyl-4-phenyl-4-propionoxypiperidine (MPPP) and 1-[2-phenylethyl]-4-phenyl-4-acetoxypiperidine (PEPAP) interacted significantly (Ki 1.6 microM and 0.3 microM, respectively). Both are synthetic analogues of meperidine sold as "synthetic heroin." No CYP2D6-mediated metabolites were detected for either compound. Concurrent oral use of CYP2D6 substrates with MPPP and PEPAP may represent a kinetic drug interaction risk, but this risk must be confirmed clinically.