An Advanced Glycation Endproduct (or AGE) is a protein or lipid that has become glycated.
Glycation is a haphazard process that impairs the normal functioning of molecules. It occurs as a result of exposure to high amounts of sugar. These AGEs are present at above average levels in people with diabetes and various ageing-related disorders, including neurodegenerative conditions. AGEs have been shown to trigger signalling pathways within cells that are associated with both oxidative stress and inflammation, but also cell death.
RAGE (or receptor of AGEs) is a molecule in a cell membrane that becomes activated when it interacts with various AGEs. And this interaction mediates AGE-associated toxicity issues. Recently researchers found that that neurons carrying the Parkinson’s associated LRRK2 G2019S genetic variant are more sensitive to AGEs than neurons without the genetic variant.
In today’s post we will look at what AGE and RAGE are, review the new LRRK2 research, and discuss how blocking RAGE could represent a future therapeutic approach for treating Parkinson’s.
The wonder of ageing. Source: Club-cleo
NOTE: Be warned, the reading of this post may get a bit confusing. We are going to be discussing ageing (as in the body getting old) as well as AGEing (the haphazard process processing of glycation). For better clarification, lower caps ‘age’ will refer to getting old, while capitalised ‘AGE’ will deal with that glycation process. I hope this helps.
Ageing means different things to different people.
For some people ageing means more years to add to your life and less activity. For others it means more medication and less hair. More wrinkles and less independence; more arthritis and less dignity; More candles, and less respect from that unruly younger generation; More… what’s that word I’m thinking of? (forgetfulness)… and what were we actually talking about?
Wisdom is supposed to come with age, but as the comedian/entertainer George Carlin once said “Age is a hell of a price to pay for wisdom”. I have to say though, that if I had ever met Mr Carlin, I would have suggested to him that I’m feeling rather ripped off!
George Carlin. Source: Thethornycroftdiatribe
Whether we like it or not, from the moment you are born, ageing is an inevitable part of our life. But this has not stopped some adventurous scientific souls from trying to understand the process, and even try to alter it in an attempt to help humans live longer.
Regardless of whether you agree with the idea of humans living longer than their specified use-by-date, some of this ageing-related research could have tremendous benefits for neurodegenerative conditions, like Parkinson’s.
What do we know about the biology of ageing?
This is Dr Henri Huchard (1844-1910; a French neurologist and cardiologist):
In 1875, he described the case was of a child who, at just 3 years of age, presented with all the clinical features of Parkinson’s disease. Since that report, there have been many studies detailing the condition that has come to be known as ‘juvenile Parkinsonism‘. Currently the youngest person diagnosed with Parkinson’s disease is a young lady from Oklahoma. She was diagnosed at 10-years of age, but had shown symptoms since the age of 2.
We are going to explore juvenile Parkinson’s disease in future post, but today’s post will review some new research that looks at the differences in Parkinson’s disease features of people diagnosed at different ages.
For most members of the general public, Parkinson’s disease is considered a condition of the elderly. And this is a fair line of thinking given what they probably observe out there in the big wide world.
A few years ago though, Parkinson’s UK commissioned and published a report of the statistics/demographics of Parkinson’s disease in the UK (Click here for a copy of that report). In that report, they present this table:
It illustrates the estimated number of people in each age bracket that have Parkinson’s disease. As you can see, the bulk of the people affected are over the age of 60. But this does not mean that Parkinson’s disease is simply a condition of the aged. It is believed that worldwide at least 5% of diagnoses are to people below the age of 50 – this is considered early onset Parkinson’s disease.
There are many people – actor Michael J Fox among them – who have been diagnosed below the age of 40.
Actor Michael J Fox was diagnosed with Parkinson’s disease at age 30.
Source: MJFox foundation
Given this wide spectrum of age of onset, it is curious that more research has not been conducted comparing the differences in features of the condition between the different age groups. This situation, however was remedied recently:
Title: Age at onset and Parkinson disease phenotype.
Authors: Pagano G, Ferrara N, Brooks DJ, Pavese N.
Journal: Neurology. 2016 Feb 10.
The investigators in this study took 422 people who had recently been diagnosed with Parkinson’s disease (none of them were on any anti-Parkinson’s medication, eg. L-dopa). The subjects were divided into 4 groups according to their age at diagnosis:
- younger than 50 years (58 subjects)
- 50-59 years (117 subjects)
- 60-69 years (168 subjects)
- older than 70 years (79 subjects)
The researchers then investigated differences in:
- side of onset (left or right; dominant or non-dominant side of the body)
- type of symptoms (rigidity or tremor, etc)
- localization of symptoms occurrence (eg. arms, legs, etc)
- severity of motor features (rigidity, tremor,…)
- severity of nonmotor features (memory, attention,…)
- severity nigrostriatal function (brain imaging of the dopamine system)
- CSF biomarkers (Chemicals in the cerebrospinal fluid which surrounds the brain)
Curiously in all of the four groups, a quarter of the people had a family history of Parkinson’s disease. Familial history could suggest a genetic connection, and the genetic aspect of Parkinson’s disease has generally been associated with the early onset group. But this does not appear to be the case in this study – there was no bias towards the younger onset group.
Asymmetry of motor features onset (eg. tremor, etc) was apparent in 97.8% of the total population, with 55% of those subjects having symptoms on their dominant side. It is interesting to note here, however, that the young onset group were the only group in which the non-dominant side was more affected than the dominant. Similarly, almost all of the symmetrical onset individuals (exhibiting no asymmetry in their motor features) were in the oldest group.
In all four groups, the arm was the more likely site of motor features (this was the case in approx. 85% in all groups). When considering other sites of onset, the head was more frequent in the older groups than the younger group, while the leg was more common in the younger group than the older group.
The older the age at onset the more severe the motor (eg. resting tremor, and postural instability scores) and nonmotor features (including autonomic, olfactory, and cognitive functions). This was accompanied by a greater dopaminergic dysfunction on the brain scan, and a reduction of alpha synuclein floating around in the cerebrospinal fluid.
Rigidity was more common in the young-onset group.
There were no differences between the groups in terms of issues associated with activities of daily living, measures of depression and anxiety, impulsive control, or sleep problems.
What does it all mean?
Why these difference exist and what they might tell us about the condition is yet to be determined. The results are interesting when one considers that the subjects had similar disease duration (they had all just been diagnosed; within 6 months of diagnosis). This suggests that the observed differences may be specific to the different age groups. A direct contribution of the aging process, however, has to be considered when assessing the older group.
This kind of analysis is necessary as it is the only way small details about the disease can be determined. We thought this was an interesting study