The atypical parkinsonian disorders present clinically with a myriad of symptoms owing to the diffuse nature of the underlying neuronal involvement. Current palliative pharmacotherapies, largely seeking to normalize resultant transmitter system abnormalities, are largely unsuccessful because of poor efficacy, prominent adverse effects, or both. A variety of factors contribute to this unfortunate situation. The number of patients afflicted by these disorders is small, insufficient to stimulate specific pharmaceutical development efforts. Attempts to rigorously assess possible extensions of existing drugs to the treatment of the atypical parkinsonian syndromes have been uncommon. There are no reliable means for early and accurate diagnosis, although the National Institutes of Health-Progressive Supranuclear Palsy (NINDS-PSP) criteria is specific. There is also a need for validated animal models, but studies are under way (102-105). Finally, most clinical trials have been so limited and poorly designed as to preclude reliable interpretation. In this setting, physicians have largely been left to make their own best therapeutic judgments. Treatment remains symptomatic and largely supportive (Table 1) while awaiting the emergence of neuroprotective strategies to slow or stop disease progression. Palliative therapies include ambulatory aids and rehabilitation, which are discussed in another chapter.
Notwithstanding the rapid advances in basic neurosciences research, the causes of neurodegenerative disease remain obscure. Without more detailed etiologic information, the probability of discovering an effective protective therapy is small. Current research implicates a complex combination of genetic predispositions and endogenous and/or environmental factors. Oxidative stress, excitotoxicity, mitochondrial deficiency, microglial activation, apoptotic triggering, and protein-processing abnormalities have all been suggested as possibly contributory (Table 2). Recently, the proteins a-synuclein, which interfere with membrane protein function, and tau, a microtubular-associated protein, which plays an important role in neuronal transport, have received increasing investigative attention. The discovery of these proteins has prompted classification of the atypical parkinsonian disorders into a-synucleopathies, specifically MSA (106,107) and DLB (108),
Possible Disease Etiologies and Areas to Explore for Neuroprotection
Oxidative stress Excitotoxicity Mitochondrial deficiency Microglial activation Apoptotic triggering
Protein processing abnormalities (i.e., accumulation of a-synuclein, tau)
and tauopathies, specifically PSP and CBD (109,110). Pathological overlap exists, however, and colocalization of a-synuclein and tau does occur (111-114). A possible role for these proteins in pathogenesis could also provide a basis for developing surrogate spinal fluid outcome measures to assist in the clinical evaluation of therapeutic candidates. Stimulation of axonal regeneration through glial cell-derived neurotrophic factor (GDNF) has already received attention. Neuroradiologic advances also promise to provide clearer insight into such matters as local cerebral blood flow, transmitter system function, and intracellular metabolic abnormalities, needed to identify the cause of the selective neurodegenerative processes and to discover successful therapeutic interventions.
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