Why we need to be able to PREDICT PD

A very simple overview of PD pathology:

Parkinson’s disease is a complex disorder, but one of the most important aspects of the pathology is the death of neurons in a region of the brain called the substantia nigra. These neurons project to the striatum, where they release a chemical called dopamine. In PD, the death of these neurons leads to reduced levels of dopamine in the striatum, which in turn results in symptoms such as slowness in movement and rigidity.

Parkinson's Disease involves death of dopamine releasing neurons which project from the substantia nigra to the caudate nucleus and putamen (collectively called the striatum)

The need for new ‘neuroprotective’ treatments

Current treatments for PD (such as levodopa) revolve around restoring striatal dopamine to normal levels. However, these drugs may cause intolerable side-effects and their effectiveness declines over time. Furthermore, these ‘dopaminergic’ therapies cannot help with symptoms which are not caused by deficits in dopamine.

The real problem is that all our current treatments are symptomatic – they address only the shortfall in dopamine levels, rather than actually providing neuroprotection (i.e. halting or reversing the process of cell death which occurs).

Why have neuroproective treatments been so hard to develop?

One of the most important reasons that neuroprotective treatments have been so hard to develop is that 70-80% of striatal dopamine is already lost by the time diagnosis is made (Fearnley & Lees, 1991; Stoessl, 2007).

 

Loss of dopaminergic (DA) neurones in the substantia nigra occurs perhaps 5-6 years before the onset of PD (solid line). If we can predict PD early, perhaps we can slow this cell loss and delay the onset of symptoms (dashed line).

This means that once we have identified patients with PD the damage has already been done and it would be too late for neuroprotective treatments to prevent the development of parkinsonian symptoms (Streffer et al, 2012).

Why are projects such as PREDICT-PD so important?

Projects like PREDICT-PD are important because being able to identify people likely to go on to develop PD will allow trials of neuroprotective therapies to be started earlier in the disease process (Postuma et al, 2010; Postuma & Montplaisir, 2009; Streffer et al, 2012). These neuroprotective treatments would then stand a much better chance of preventing or slowing the onset of PD.

How might we be able to predict PD?

Fortunately, there may be some clues as to an individual’s risk of PD which emerge before the onset of sympotms. PD is believed to have a ‘prodromal’ phase where non-motor symptoms (such as smell loss and depression) or even very subtle motor symptoms may emerge, before the full onset of the disease (Hawkes, 2008; Postuma et al, 2012a). These prodromal symptoms include:

• Non-motor symptoms 
• Loss of smell (Shah et al., 2009)
• Depression (Reijnders et al, 2008)
• 'Autonomic' nervous system dysfunction
• Constipation (Abott et al, 2001; Savica et al, 2009)
• Variability in heart rate and other cardiac autonomic abnormalities (Palma et al, 2013)
• Sleep problems (Boeve, 2013; Videnovic & Golombek, 2013)
• Cognitive impairment (Aarsland et al, 2010; Williams-Gray et al 2013)
• Problems with vision (Postuma et al, 2012a)
•  Subtle motor symptoms - slowed movment, tremor etc. (Postuma et al 2012b)

There are also environmental and genetic risk factors for PD – such as exposure to pesiticides (which increases risk of PD) smoking or coffee drinking (which decrease risk of PD), family history of PD (genetic risk factors) or previous head injury (Noyce et al, 2012). 

Combining information on risk of PD across all these different areas may allow the disease to be accurately predicted and for disease-modifying treatments to be started much earlier in the disease course, where they are more likely to provide beneficial effects.

For more information on how the PREDICT-PD project is going about achieving this, click here.

Jargon buster:

Substantia nigra: a region of the midbrain containing neurons which project to the striatum, where they release dopamine

Striatum: a region of the brain involved in control of movement (including starting and stoping movements) in addition to other functions

Dopamine: a neurotramsitter (a signalling chemical used by neurons to communicate with one another) whose levels are reduced in PD

Prodrome: an early symptom or group of symptoms which may indicate the start of a disease before the classically defined onset of that disease e.g. a rash which may occur before the onset of an infectious disease or the loss of smell which may occur prior to developing PD

Autonomic nervouss ystem: the division of the nervous system which controls bodily functions such as heart rate, breathing rate, digestion, urination and sexual functions.

References:

Aarsland D, Bronnick K, Williams-Gray C, Weintraub D, Marder K, Kulisevsky J, Burn D, Barone P, Pagonabarraga J, Allcock L, Santangelo G, Foltynie T, Janvin C, Larsen JP, Barker RA, Emre M (2010) Mild cognitive impairment in Parkinson disease: a multicenter pooled analysis. Neurology 75: 1062-1069

Abbott RD, Petrovitch H, White LR, Masaki KH, Tanner CM, Curb JD, Grandinetti A, Blanchette PL, Popper JS, Ross GW (2001) Frequency of bowel movements and the future risk of Parkinson's disease. Neurology 57: 456-462

Boeve BF (2013) Idiopathic REM sleep behaviour disorder in the development of Parkinson's disease. Lancet Neurol 12: 469-482

Fearnley JM, Lees AJ (1991) Ageing and Parkinson's disease: substantia nigra regional selectivity. Brain 114 ( Pt 5): 2283-2301

Hawkes CH (2008) The prodromal phase of sporadic Parkinson's disease: does it exist and if so how long is it? Mov Disord 23: 1799-1807

Noyce AJ, Bestwick JP, Silveira-Moriyama L, Hawkes CH, Giovannoni G, Lees AJ, Schrag A (2012) Meta-analysis of early nonmotor features and risk factors for Parkinson disease. Ann Neurol 72: 893-901

Palma JA, Carmona-Abellan MM, Barriobero N, Trevino-Peinado C et al. (2013) Is cardiac function impaired in premotor Parkinson's disease? a retrospective cohort study. Mov Disord 28: 591-596

Postuma RB, Aarsland D, Barone P, Burn DJ, Hawkes CH, Oertel W, Ziemssen T (2012a) Identifying prodromal Parkinson's disease: pre-motor disorders in Parkinson's disease. Mov Disord 27: 617-626

Postuma RB, Gagnon JF, Montplaisir J (2010) Clinical prediction of Parkinson's disease: planning for the age of neuroprotection. J Neurol Neurosurg Psychiatry 81: 1008-1013

Postuma RB, Lang AE, Gagnon JF, Pelletier A, Montplaisir JY (2012b) How does parkinsonism start? Prodromal parkinsonism motor changes in idiopathic REM sleep behaviour disorder. Brain 135: 1860-1870

Postuma RB, Montplaisir J (2009) Predicting Parkinson's disease - why, when, and how? Parkinsonism Relat Disord 15 Suppl 3: S105-109

Reijnders JS, Ehrt U, Weber WE, Aarsland D, Leentjens AF (2008) A systematic review of prevalence studies of depression in Parkinson's disease. Mov Disord 23: 183-189; quiz 313

Savica R, Carlin JM, Grossardt BR, Bower JH, Ahlskog JE, Maraganore DM, Bharucha AE, Rocca WA (2009) Medical records documentation of constipation preceding Parkinson disease: A case-control study. Neurology 73: 1752-1758

Shah M, Deeb J, Fernando M, Noyce A, Visentin E, Findley LJ, Hawkes CH (2009) Abnormality of taste and smell in Parkinson's disease. Parkinsonism Relat Disord 15: 232-237

Stoessl AJ (2007) Positron emission tomography in premotor Parkinson's disease. Parkinsonism Relat Disord 13 Suppl 3: S421-424

Streffer JR, Grachev ID, Fitzer-Attas C, Gomez-Mancilla B, Boroojerdi B, Bronzova J, Ostrowitzki S, Victor SJ, Fontoura P, Alexander R (2012) Prerequisites to launch neuroprotective trials in Parkinson's disease: an industry perspective. Mov Disord 27: 651-655

Videnovic A, Golombek D (2013) Circadian and sleep disorders in Parkinson's disease. Exp Neurol 243: 45-56

Williams-Gray CH, Mason SL, Evans JR, Foltynie T, Brayne C, Robbins TW, Barker RA (2013) The CamPaIGN study of Parkinson's disease: 10-year outlook in an incident population-based cohort. J Neurol Neurosurg Psychiatry