June 2, 2015

Parkinson’s Disease: The Long Journey from Physical Ailment to Something Much More Complicated


In 1817, James Parkinson published “An Essay on the Shaking Palsy.” He had observed several classic symptoms – tremor, rigidity, postural instability – in a very small group: three of his own patients and three people on the streets of London.

His essay gained little attention. But in 1861, French neurologist Jean Martin Charcot and several colleagues distinguished the disease from other neurological conditions and named it “Parkinson’s disease” (PD).

While Parkinson had the notion that the disease developed in the brain, for a long time it was considered a simpler collection of physical malfunctions.

In 1879, doctoral candidate Paul de Saint-Leger’s used the woodcuts (shown at the top of this post) of the hunched man to illustrate his thesis “Paralysie agistante.” What’s on display is the clear physical manifestation of a PD patient with postural instability and shuffling gait.

Not much more was understood about the disease at the time. And it would take many more decades before the disease – and the science behind it – were understood more fully.

I recently saw a brief essay -- "Parkinson's disease: the flip side of the coin" -- on OUPblog, "Oxford University Press's Academic Insights for the Thinking World." The author is Murat Emre, professor of neurology at the Istanbul Faculty of Medicine, Istanbul University, Turkey, where he chairs the Behavioral Neurology and Movement Disorders Unit. In the piece, Emre quickly traces the evolution of our understanding of PD.

He makes a number of points, including these:
  • PD was first considered a motor disorder with – eventually – impaired mental function.
  • Effective treatments eventually extended the lives of people with PD. As a result, the cognitive effects of the disease became more apparent.
  • More recent research has established dementia and cognitive impairment as integral features of PD. Careful attention to mental slippage can even help diagnosticians identify PD in its early stages, in the same way that other non-motor symptoms – including loss of smell and depression -- can herald the presence and development of the disease.
  • Dementias that follow PD were once thought to be independent, co-incident forms of Alzheimer’s. Now, research shows that dementias associated with Parkinson’s disease (PD-D) have their own unique biochemical and pathological features, which have become markers for specific drugs – now becoming  available -- that target PD-D.

Emre wraps up his essay in this positive way:

We have entered a new phase in Parkinson’s disease research: its molecular pathology is being disentangled; the first vaccination trial is on the way along with efforts to in vivo image the accumulation of alpha synuclein molecules, the hallmark pathological feature of PD. We are looking forward to exciting times, which we hope to come sooner rather than later.

Here’s the full text of Emre’s article:

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The human brain might be perceived as an organ with two main strategic tasks: goal-directed motor behavior, and mental functioning in order to work out that goal. These two main functions have two prototypical diseases: Alzheimer disease, in case of mental function, and Parkinson’s disease, with motor function.

Following its inception as an entity, Parkinson’s disease (PD) was long perceived to be a purely motor disorder with unimpaired mental functions. This was partly influenced by its initial description by James Parkinson, who wrote that the intellect and senses remain intact. Although some of his contemporaries challenged this view and suggested that mental functions do get impaired in patients with advanced PD, this observation did not receive much attention for many decades. It’s ironic that modern medical treatment, which has dramatically changed the lives of PD patients, came as a mixed blessing; trading effective management of motor symptoms and longer patient survival with mental dysfunction (and some other non-motor features of the disease) becoming more apparent

Research in the last few decades has established that cognitive impairment and dementia are an integral part of the disease process. Several prospective as well as cross-sectional studies revealed that milder forms of cognitive impairment can even be detected at the early stages of the disease, if appropriately looked for. In fact, it has become apparent that some non-motor symptoms may precede classical motor symptoms by many years, such as anosmia, depression, constipation and dream-enacting behavior. When properly assessed, a variety of non-motor symptoms can be identified throughout the disease. Dementia develops particularly in patients with advanced age and severe disease; twenty years after the diagnosis, mental dysfunction of varying degrees is present in practically all patients.

In earlier years the assumption was that dementia in PD may simply represent co-incident Alzheimer disease (AD). Research on the profile of dementia associated with PD (PD-D), however, demonstrated that, in a typical patient, its features are different than that of AD, and it constitutes a dementia syndrome of its own. Biochemical deficits and pathological features associated with PD-D were also worked out, which lead to the first rationally designed treatment trials. These studies bore fruit and the first specific drug for PD-D became available. In parallel, clinical diagnostic criteria were described for PD-D as well as criteria for mild cognitive impairment associated with PD (PD-MCI). Efforts are now ongoing to better understand the neurobiological basis of cognitive impairment and to find biomarkers which can identify patients at risk in earlier stages. Once the chrono-biology of mechanisms are better understood, scientists may be able to design treatment interventions to halt the progression of mental dysfunction, as well as the progression of the disease itself.

We have entered a new phase in Parkinson’s disease research: its molecular pathology is being disentangled; the first vaccination trial is on the way along with efforts to in vivo image the accumulation of alpha synuclein molecules, the hallmark pathological feature of PD. We are looking forward to exciting times, which we hope to come sooner rather than later.

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