PARKINSON'S DISEASE: FAR MORE THAN A MOVEMENT DISORDER

By Douglas F. Watt, Ph.D.

Adjunct Professor, Graduate Department of Psychology Lesley University

Clinical Neuroscience Advisor, 9th Dimension Biotech, Inc.

In this review we will cover the basic epidemiology, genetics, environmental risk factors and neurobiology associated with PD, with an eye towards examining alpha synuclein, its promoting interactions with both inflammation and mitochondrial decline, and why substantia nigra DA neurons might be particularly vulnerable in PD – a core aspect of the PD phenotype still not fully explained.  Recent work suggests a heightened vulnerability in those nigral DA systems to age-related changes and to the effects of alpha synuclein, associated with their enormously long axons, huge dendritic trees, and special forms of calcium processing and mitochondrial vulnerability.   

Like we saw with AD, we will see evidence that declining and eventually failing autophagy proceeds clinical stages, (but unlike AD?), the disease may start outside the CNS proper, in the enteric nervous system, as well as in olfactory systems.  Like AD, and explaining its pattern of spread, there is evidence for a prion-like seeding mechanism for aggregates of alpha synuclein and again like AD, oligomers may have unique toxicities compared to other assembly states.  Also like AD, the pathognomonic and pathogenic protein alpha synuclein may be upregulated in aging while also intrinsically blocking autophagy systems and thus may be intrinsically difficult to clear (just like amyloid).  

All this suggests a deep shared vulnerability in aging to neurodegenerative disorders around the upregulation of proteins which help compensate for age-related change in neural networks that just happen to be autophagy-inhibiting.  In other words, slim margins around these proteins, in terms of the system's ability to clear them in the first place, may be all too easily exceeded in the context of numerous environmental and genetic risk factors.  This shared preclinical mechanism of autophagy failure sets the stage for what takes place in the clinical stages of PD where Lewy bodies and progressive dopaminergic loss impacting systems beyond the putamen (such as the caudate which has almost entirely cognitive functions) characterize the shifts from preclinical to early clinical to late clinical phenotypes.  We will also discuss the difficult differential diagnosis between PD and so-called Parkinsonian Plus Disorders such as progressive supranuclear palsy, striatal-nigral degeneration, and multiple system atrophy, which can also show synucleinopathy.  Once again emerging work on biomarkers may help along with careful attention to symptoms “at the margins”.  Remaining questions include what might differentiate classic PD from more diffuse Lewy body disease.  Is this a clear bifurcation or a rough continuum?

Implications for both prevention and treatment will be explored, and once again, we currently lack well validated strategies for both more highly effective prevention and for better neuroprotection in clinical stage patients, once progressive degeneration of nigral DA systems is underway.  Treatment for early clinical stage patients is ameliorative but modestly to reasonably effective, at least in relationship to classic motor issues, and L-dopa may even have modest neuroprotective effects, although this is still debated.  Cognitive, affective, and other nonmotor symptoms are often times neglected in the clinical treatment equation, under the paradigm that PD is a movement disorder, a meme that obscures and obfuscates PD's considerable depressogenic and cognition-eroding impact.  This neglect is regrettable, but it points to the need for more concerted focus both in research and clinical care on nonmotor issues, which is slowly happening, and better education for all the relevant clinical disciplines.  Do CR mimetics (which may be antidepressant), deep brain stimulators or other innovative treatments offer promise (treatment issues in PART 2)? 

By Douglas F. Watt, Ph.D.

Adjunct Professor, Graduate Department of Psychology Lesley University

Clinical Neuroscience Advisor, 9th Dimension Biotech, Inc. 

In part I, we summarized basic epidemiology, diagnostic criteria, and the differential diagnosis of classic PD versus diffuse Lewy body disease versus Parkinsonian plus disorders, along with a basic circuit topography in terms of what happens to the neo-striatal basal ganglia circuits when progressively deprived of dopamine. We will circle back briefly to one confusing section in that first talk, just to clear up a couple of issues and then begin a systematic exploration of a host of remaining issues – and those include the most troubling questions about PD around mechanism and pathogenesis.

First, we will talk briefly about the genetics of PD, and how there are both more deterministic and merely higher risk gene endowments, much as we saw with Alzheimer's disease.  We will review – in at least a cursory fashion – current treatment paradigms including classic L-dopa, dopamine agonists, and DBS.  We will also briefly summarize major animal models, and the troubling parallels with much of AD research, where numerous interventions effective in several of those animal models have not proven effective in clinical PD.  This raises a bunch of questions which we will explore in greater detail.

Fundamental questions include: 1) is it more sensible to continue to approach Parkinson's disease from a “lumper's” or a “splitter's” point of view?  Is the obvious clinical diversity of PD better integrated under one umbrella, or should we aim for more consistent molecular and genetic subtyping to allow more precisely targeted and rational treatments?  Does an overly ‘lumping’ diagnostic paradigm explain the numerous treatment failures of putative disease modifying agents when in fact a single agent is being used to treat what may be mechanistically “different enough” diseases?  Or do the failures simply suggest that we have not penetrated into the true drivers of neurodegeneration?  These remain unanswered questions.  

Additionally, there is evidence that – just like with Alzheimer's disease – basic proteinopathy concepts (that the entire neurodegenerative process can be conceptualized as downstream effects of ‘toxic’ proteins) may leave out critical aspects of pathogenesis, including how proteinopathy may activate several secondary/compensatory processes that are not simply ‘reeled back’ by removal of toxic protein.  Just as with AD in relationship to amyloid moieties, recent monoclonal antibodies directed at alpha synuclein have failed their primary endpoints.  What does this say about our proteinopathy concepts and their core assumptions?  We will look at how proteinopathy might interact with other cellular phenotypes of aging, namely destructive inflammation/dysregulation of the innate immune system, and mitochondrial dysfunction, and what might explain the unique vulnerability of nigral dopaminergic neurons.  Indeed there is decent evidence that mitochondrial dysfunction and failure may be more central in PD than in some other neurodegenerative disorders, given that several of the genes mutated in familial PD are critical to mitochondrial function.  This recognition may however also support cautious optimism about exercise and CR mimetics as therapies given their offering a kind of ‘primary mitochondrial support,’ along with attenuation of inflammation, promotion of sleep, promotion of autophagy and mitigation of many other classic aging cellular phenotypes.

We will summarize interesting novel treatments including a recent report just earlier this year of a novel tyrosine kinase inhibitor that appears neuroprotective (again with parallels to recent findings in AD), along with initial animal model work showing neuroprotective effects of cinnamon in a synucleinopathy.  There appears to have been virtually no work on CR mimetics in PD other than glucagon like peptide agonists where animal model work has been promising, and where opinion is leading towards regular exercise as a recommended intervention.  Once again, treatment in clinical PD may need to be staged, and we may need to move away from our assumption that a single treatment should suffice if it's a really good one.  Standard treatment emphasizing compensatory dopaminergic therapies appears to have virtually no substantive or long-term neuroprotective, disease-modifying value, suggesting that disease modification will need to think outside the box of conventional dopaminergic pharmacology.  Clinicians working in PD must also expand their traditional monocular focus on motor issues to encompass cognitive, affective, and other troubling challenges in this complex disease of aging.