Parkinson Disease: Henchcliffe C

Henchcliffe C, Shungu DC, Mao X, Huang C, Nirenberg MJ, Jenkins BG, Beal MF. · Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10021, USA. · Ann N Y Acad Sci. · Pubmed #19076443 No free full text.

Abstract: Parkinson's disease (PD) is a common and often devastating neurodegenerative disease affecting up to one million individuals in the United States alone. Multiple lines of evidence support mitochondrial dysfunction as a primary or secondary event in PD pathogenesis; a better understanding, therefore, of how mitochondrial function is altered in vivo in brain tissue in PD is a critical step toward developing potential PD biomarkers. In vivo study of mitochondrial metabolism in human subjects has previously been technically challenging. However, proton and phosphorus magnetic resonance spectroscopy ((1)H and (31)P MRS) are powerful noninvasive techniques that allow evaluation in vivo of lactate, a marker of anaerobic glycolysis, and high energy phosphates, such as adenosine triphosphate and phosphocreatine, directly reflecting mitochondrial function. This article reviews previous (1)H and (31)P MRS studies in PD, which demonstrate metabolic abnormalities consistent with mitochondrial dysfunction, and then presents recent (1)H MRS data revealing abnormally elevated lactate levels in PD subjects.

Henchcliffe C, Beal MF. · Department of Neurology and Neuroscience at the Weill Medical College of Cornell University, New York, NY 10021, USA. · Nat Clin Pract Neurol. · Pubmed #18978800 No free full text.

Abstract: Parkinson disease (PD) is associated with progressive loss of dopaminergic neurons in the substantia nigra, as well as with more-widespread neuronal changes that cause complex and variable motor and nonmotor symptoms. Recent rapid advances in PD genetics have revealed a prominent role for mitochondrial dysfunction in the pathogenesis of the disease, and the products of several PD-associated genes, including SNCA, Parkin, PINK1, DJ-1, LRRK2 and HTR2A, show a degree of localization to the mitochondria under certain conditions. Impaired mitochondrial function is likely to increase oxidative stress and might render cells more vulnerable to this and other related processes, including excitotoxicity. The mitochondria, therefore, represent a highly promising target for the development of disease biomarkers by use of genetic, biochemical and bioimaging approaches. Novel therapeutic interventions that modify mitochondrial function are currently under development, and a large phase III clinical trial is underway to examine whether high-dose oral coenzyme Q10 will slow disease progression. In this Review, we examine evidence for the roles of mitochondrial dysfunction and increased oxidative stress in the neuronal loss that leads to PD and discuss how this knowledge might further improve patient management and aid in the development of 'mitochondrial therapy' for PD.

Henchcliffe C, Schumacher HC, Burgut FT. · Weill Medical College of Cornell University, Department of Neurology and Neuroscience, 428 East 72, Street, Suite 400, NY 10021, USA. · Expert Rev Neurother. · Pubmed #16274338 No free full text.

Abstract: Monoamine oxidase inhibitors inhibit dopamine metabolism and are therefore effective in treating Parkinson's disease, a condition associated with progressive striatal dopamine deficiency secondary to degeneration of dopaminergic neurons in the substantia nigra. Selegiline is currently the most widely used monoamine oxidase-B inhibitor for Parkinson's disease, but has a low and variable bioavailability, and is metabolized to L-methamphetamine and L-amphetamine that carry a risk for potential neurotoxicity. There are two new approaches that circumvent these potential disadvantages. First, selegiline orally disintegrating tablets provide a novel delivery form of selegiline, avoiding first pass metabolism by rapid absorption through the oral mucosa, thus leading to significantly lower plasma concentrations of L-metamphetamine and L-amphetamine. Selegiline orally disintegrating tablets prove to be clinically effective and safe in patients with moderately advanced Parkinson's disease. Second, rasagiline is a new monoamine oxidase inhibitor, without known neurotoxic metabolites. In large clinical trials, rasagiline proves effective as monotherapy in early Parkinson's disease, as well as adjunctive therapy to levodopa in advanced disease. Clinical data suggest, in addition, a disease-modifying effect of rasagiline that may correlate with neuroprotective activity of monoamine oxidase-B inhibitors in animal models of Parkinson's disease.

Henchcliffe C, Waters C. · The Neurological Institute, Columbia Presbyterian Medical Center, New York, NY 10032, USA. · Expert Opin Pharmacother. · Pubmed #12083995 No free full text.

Abstract: Entacapone is one of a new class of drugs, the catechol-O-methyltransferase (COMT) inhibitors, which expand the therapeutic options for Parkinson's disease by extending the action of levodopa. Entacapone is used in conjunction with levodopa and provides benefit to patients who suffer from motor fluctuations. Side effects include worsening of the dyskinesias associated with peak doses of levodopa, hypotension, constipation and urine discoloration. Unlike tolcapone, an earlier COMT inhibitor, entacapone does not require liver function monitoring.

Louis ED, Henchcliffe C, Bateman BT, Schumacher C. · GH Sergievsky Center, New York, NY, USA. · Neuroepidemiology. · Pubmed #17898522 No free full text.

Abstract: BACKGROUND/AIMS: 10% of Parkinson's disease (PD) patients have young-onset PD (YOPD). We compared YOPD patients to control patients in terms of hospital utilization and outcomes and medical comorbidities during hospitalization. METHODS: The Nationwide Inpatient Sample (NIS) provides yearly data on hospital admissions and discharges from approximately 1,000 hospitals. NIS data sets (1998-2003) were used to identify persons aged 18-40 years, including 714 PD patients and 2,007 randomly selected control patients (1:3 matching). RESULTS: Hospital length of stay (p < 0.001) and number of discharge diagnoses (p < 0.001) were higher in PD patients than controls. PD patients were more likely than controls to be discharged to a short-term hospital (odds ratio, OR, 2.23, 95% confidence interval, CI, 1.30-3.84, p = 0.004) or a skilled nursing facility (OR 4.14, 95% CI 3.06-5.61, p < 0.001); 20.4% required transfer to a short-term hospital or another facility. The most common discharge Diagnosis-Related Group code in PD patients was psychosis (23% of patients) whereas pneumonia and hip or pelvic fractures were not associated with PD. CONCLUSIONS: YOPD patients had greater healthcare utilization and hospital morbidity than controls. Upon discharge, 1 in 5 required transfer to a short-term hospital or another facility. Psychosis was the most common comorbidity whereas several comorbidities associated with older PD patients were not common.

Ries V, Henchcliffe C, Kareva T, Rzhetskaya M, Bland R, During MJ, Kholodilov N, Burke RE. · Department of Neurology, Columbia University College of Physicians and Surgeons, 650 West 168th Street, New York, NY 10032, USA. · Proc Natl Acad Sci U S A. · Pubmed #17116866 links to  free full text

Abstract: Despite promising preclinical studies, neurotrophic factors have not yet achieved an established role in the treatment of human neurodegenerative diseases. One impediment has been the difficulty in providing these macromolecules in sufficient quantity and duration at affected sites. An alternative approach is to directly activate, by viral vector transduction, intracellular signaling pathways that mediate neurotrophic effects. We have evaluated this approach in dopamine neurons of the substantia nigra, neurons affected in Parkinson's disease, by adeno-associated virus 1 transduction with a gene encoding a myristoylated, constitutively active form of the oncoprotein Akt/PKB. Adeno-associated virus Myr-Akt has pronounced trophic effects on dopamine neurons of adult and aged mice, including increases in neuron size, phenotypic markers, and sprouting. Transduction confers almost complete protection against apoptotic cell death in a highly destructive neurotoxin model. Activation of intracellular neurotrophic signaling pathways by vector transfer is a feasible approach to neuroprotection and restorative treatment of neurodegenerative disease.

Oo TF, Henchcliffe C, James D, Burke RE. · Department of Neurology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA. · J Neurochem. · Pubmed #9930727 No free full text.

Abstract: The transcription factors c-fos and c-jun have been proposed to play a role in the initiation of programmed cell death in neurons. We have shown that programmed cell death, with the morphology of apoptosis, occurs in dopamine neurons of the substantia nigra (SN) during normal postnatal development and that this death event can be induced by early striatal target injury. We have investigated the relationship between c-fos and c-jun protein expression and induced death in neurons of the SN. Although c-fos is induced, it is unlikely to play a role in cell death, because its expression is not well correlated with apoptotic death either temporally or at a cellular level. Expression of c-jun, however, is both temporally and regionally correlated with induction of death, and, at a cellular level, it colocalizes with apoptotic morphology. The increased expression of c-jun is likely to be functionally significant, because it is associated with increased c-jun N-terminal kinase (JNK) and phosphorylated c-jun expression. JNK expression also colocalizes with apoptotic morphology. We conclude that c-jun is likely to play a role in the initiation of apoptotic cell death in these neurons.