Coastal Neurological
Medical Group, Inc.

NEW ADVANCES IN PARKINSON’S DISEASE

DEE SILVER M.D.

New treatment falls in several groups. The first is oral medications that are in development. They may be symptomatic or neuroprotective. One pharmacological agent now being investigated in clinical trials is an adenosine 2A(A2a) antagonist called preladenant. The A2a receptor is located in the striatum on GABA enkephalin medium spiny neurons and antagonism on these receptors is thought to reduce hyperexcitability that occurs. A drug with similar mechanisms of action (istradefylline) was studied before with uncertain results and has never released. Preladenant in early trials has been able to reduce “off” time in fluctuators on L-dopa by two hours. Glutamate antagonists are also being studied in clinical trials. Mementine is a glutamate antagonist used in the treatment of Alzheimer’s disease. Serotonin receptor antagonists are also being studied for the treatment of neuropsychritic symptoms. Oral agents for the use as neuroprotection are in clinical trials such as creatine, drugs to increase uric acid, calcium channel blockers, and a peroxisone proliferator activated receptor agonist (piolitazone). Gene therapy has shown good result in animal models but yet has to be associated with robust clinical results in patients. A viral vector is used to deliver the agent into the brain. Adeno-associated viral vector encoding glutamic acid decarboxylase has been placed into the brain but the results are uncertain. Also gene transfers with trophic factors (GDNF) have been used in clinical trials. Aromatic amino acid decarboxylase has been placed in the brain also. Also a cocktail of enzymes have been transferred by a lentivial vector. All of the gene therapy approaches are very early in their development.

Sequencing the genome took 13 years, 3 billion dollars and now costs about two thousand dollars to sequence. In most cases you will get data but will not be able to do anything about it. Acting on gene information and guiding drug therapy is not yet possible in most patients. Genes code proteins and mutations may change the process and the protein. There are 6 billion letters in the gemone. 23 & Me is a testing program that is available for Parkinson patients and uses saliva to analyze. It is genotyping and it is not DNA sequencing. 23 & Me is an odds calculator and gives you percent chance information and it is a probability consideration. Actionable genes are genes that you may be able to do something about. There are now some 200 to 250 actionable genes. For example genes associated with heart disease, breast cancer, melanoma, and thrombotic disease.

A Cutaneous marker for IPD may be possible by doing a biopsy of the skin and seeing alpha synuclein in pilomotor and sympathetic cholinergic fibers.

Exercise with Nintendo Wii 1 hour 3 times a week improved gait, balance and motor scores in 40 patients. It has been shown that exercise delays postural instability and dyskinesia in a retrospective study in IPD.

Rasagiline incubated in cells reduced the aggregation of alpha synuclein. Depression and poor motor function are closely related and less so to age and dementia. Depression and quality of life are closely related. Depression and anxiety are under diagnosised in IPD. Smoking and caffeine affect genes and may give mutations.

A test rating scale called the PDQ39 correlates with care giver burden and the higher burden gives greater depression for caregiver. Patients with diabetes and IPD as compared to IPD without diabetes had greater akinesia and gait difficulty but no more tremors. Men have more rigidity, bradykinesia and gait disturbances than females. The reason is uncertain but being female may give questionable protective effect.

In CSF increased tau and decreased beta amyloid shows a pattern in some diseases and has a ranking as follows; DAT>DLB >PDD>IPD.

Small fiber neuropathy in IPD affects sensor and autonomic fibers. Patients with Frontal Temporal Dementia and Parkinsonism with Ch 9 have mutations in tau (MAPT), progranulin (PGRN), and hexosudeolide repeat expansion and clinically have rigidity, akinesia, with symmetry.

Essential Tremor patients have more RBD and depression than controls. PDD patients have more white matter hyper intensities and more cognitive impairment. Always check for B12, folic acid, and homocysteine to look for possible treatable disease.

MSA patients have a rapid progression and clinically have Parkinsonism, cerebellar ataxia and autonomic failure. Micturition urgency, othrostatic hypotension, cold hands and feet and hypophonia also occur. Dysphagia and falls and cranial dystonia are also seen. The MRI shows putaminal atrophy, hyper intense rim and a hot cross buns sign. The average survival is 6 years.

Vascular dementia has its onset on average at 68 and has more rigidity and akinesia with symmetry.

With closed head injury (CHI) the odds ratio for developing Parkinson’s is 1.6. A relatively new finding is the Glucocerebrasidase gene is associated with Parkinsonism.

L-dopa intestinal gel is given via a tube implanted in the small bowel and given by a portable pump. Phase 3 trials shows 1.9 hours of “off” time reduced over l-dopa orally. Adverse effects were device complications 51%, abdominal pain 42%, and nausea 25%, wound infection 17%, and wound erythema 16%.

Oral dipraglurant for dyskinesias gave 70 minutes more “On” time without dyskinesias and 50 minutes less “Off” time when compared to placebo. Pardoprunox a partial dopamine agonist and fully stimulating serotonin receptor agent reduced “Off” time by 45 minutes. A new Pro drug XP21279 which is converted to L-dopa gave more “On” and less “Off” time. Monoclonal antibodies were used to reduce alpha synuclein in animal models and will soon be studied in patients with IPD. CLR 01 is being used to inhibit the alpha synuclein aggregation in cell cultures, Zebra fish and animal models.

DBS with placement of electrodes in the Gpi and the STN cell groups is the most common site for placement of electrodes. These are hyper excitable or have hyper synchrony and have B eta activity. This Beta activity can be recorded with surface electrodes. This beta activity is increased in IPD patients with movement and attenuates with medication. To improve the patients clinical state, DBS must over ride this hypersynchrony, or attenuate the Beta activity. The optimal site for the electrodes in the STN is in the dorsal area or just above in the axonal pathway. Most of these out flow pathways are to the palladium and the brainstem which become part of the sensorimotor network. This attenuation may be acting on the cortex indirectly. Electrode placement in the STN will give various adverse effects. Too medial will give mood changes and too lateral or anterior and too deep will give depression. Too medial and deep will give mood and cognitive changes. Monopolar and bipolar recordings are the most used but double monopolar is being used more. A technique called interleaving can be used to overlap electrode sites. After DBS never have an MRI below the neck since the intracranial electrodes maybe heated and cause cellular damage.

Dee Silver M.D. 5/30/12

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Coastal Neurological Medical Group
9850 Genesee Avenue
Suite 860
La Jolla, CA 92037
Tel: 858.453.3842
Fax: 858.535.9390

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