Parkinson’s disease (PD), the most common form of movement disorder and the second most common neurodegenerative disorder, is characterized by loss of dopaminergic neurons in the substantia nigra pars compacta, leading to various cardinal motor symptoms such as resting tremor, rigidity, bradykinesia and postural instability, which become progressively worse as the disease advances. Through the course of disease, the heterogeneity of symptoms among patients is reflected by two major subtypes: tremor-dominant and akinetic-rigid. In addition, some non-motor symptoms such as altered olfactory function, erectile dysfunction, mood and sleep disturbances, pain, autonomic, gastrointestinal, neuropsychiatric and sensory symptoms etc may occur prior to the onset of motor symptoms.
The Unified Parkinson's Disease Rating Scale (UPDRS) Motor Examination (part III) measures motor symptoms, with higher scores suggesting a greater severity of the disease. Neuroimaging data and pathological reports have been shown that tremor-dominant patients present a slower progression in which there is better preservation of the nigro-striatal pathway, whereas a faster progression occurs in the akinetic-rigid type that is accompanied by severe cell loss in the substantia nigra pars compacta. Fluoropropyl-carbomethoxy-iodophenyl-tropane (FP-CIT) single photon emission computed tomography (SPECT), a sensitive tool for quantifying the striatal density of the dopamine transporter, is also used clinically to evaluate PD. Tremor-dominated patients have been seen to show consistently higher FP-CIT uptake in all the examined regions as compared to the akinetic-rigid group.
Dopamine-replacement therapy (levodopa and dopamine agonists) improves the motor symptoms and diminishes the disability. However, the benefits of higher doses are offset by the side effects, such as hallucination, confusion, and motor complications, which are broadly classified as “wearing –off reactions”, “on-off reactions” and dyskinesia. Levodopa is transformed into dopamine in the brain to replenish the brain’s dwindling supply. Furthermore, surgical treatments such as pallidotomy, thalamotomy, subthalamotomy and high-frequency deep-brain stimulation (DBS) via electrodes implanted in the globus pallidus, thalamus or sub-thalamic nucleus have reportedly been effective in reducing symptoms and improving function. However, non-motor symptoms are not completely responsive to dopaminergic medication, suggesting that the non-motor symptoms might be mediated by non-dopaminergic pathways and non-nigro striatal mechanisms such as neurodegeneration of other transmitter system in the cortex and brainstem as well as genetic and psychosocial factors.
Among the cardinal motor symptoms, tremor, bradykinesia and rigidity are most responsive to dopaminergic medication and surgical treatment. Numerous exercise interventions (e.g., aerobic exercise, home-based exercise intervention, treadmill training with bodyweight support and resistance training etc) and rehabilitation programs have emerged to alleviate the occurrence of falls and gait dysfunctions associated with postural disability.
A few putative agents for neuroprotection and disease modification have been tested in clinical trials and others are on the way. The first prospective clinical trial was done using the novel approach of Rasagiline for disease modification. It is an irreversible monoamine oxidase type -B (MAO-B) inhibitor. It is found to show a consistently slower rate of worsening in the UPDRS scores associated with early-start treatment with Rasagiline at 1 mg per day. However, a therapeutic agent with strong disease-modifying effects is not available.
Reference:
Ruiping Xia; Zhi-Hong Mao (2012). Progression of motor symptoms in Parkinson’s disease. , 28(1), 39–48. doi:10.1007/s12264-012-1050-z
Comments