Ask the Expert: Progression Rates To Clinical Milestones In Parkinson’s

In diseases like LBD, Parkinson’s or Alzheimer’s, the ability to predict disease progression helps physicians anticipate clinical care needs and allows families put their experiences into context. Understanding the natural history of these conditions also prepares families to have important discussions about life goals and personal care needs. A new study reports on 3 key milestones that have the greatest impact on individuals with Parkinson’s disease (PD): postural instability, onset of dementia, and mortality.

The CamPaIGN study (Cambridgeshire Parkinson’s Incidence from GP to Neurologist) is the first study to follow individuals who were newly diagnosed with PD in one community over time. This ‘unbiased’ group provides a more accurate picture of the progression of Parkinson’s disease, compared to studying individuals seeking care in a specialty setting, who are often more challenging cases. The CamPaIGN study provides a comprehensive picture about the natural progression of Parkinson’s disease.

Dr. Caroline Williams-Gray from the University of Cambridge, UK, and colleagues followed 142 individuals from the time of diagnosis over 10 years. The study included a core cohort of 121 individuals in whom a diagnosis of PD was reconfirmed at a second visit at 3.5 years, thus increasing the likelihood of accurate diagnosis. Another 21 individuals were included who met diagnostic criteria for PD initially but either died (14) or withdrew (7) prior to the second diagnostic review. All individuals underwent extensive medical histories, clinical and neuropsychological tests, and DNA testing. The mean age of diagnosis was 70.2 years.

Previous research published on this study at 3.5, 5 and 7 year intervals from diagnosis reveals that movement and cognitive symptom progression in PD varies from person to person. Some people developed dementia early, especially those who were older, had decline in certain tests of language and visuospatial skills, and those with a specific genetic variation in a gene called ‘tau’. Interestingly, impairment in ‘executive’ cognitive function, like problem solving and analytical thinking, did not predict a later progression to dementia. Axial motor symptoms, including problems with balance and walking, did not tend to respond well to Parkinson’s medication and are a useful indicator of disease progression. When individuals reach a stage where they have lost normal balance reflexes, they tend to fall frequently, and this ‘postural instability’ was found to be a major milestone in Parkinson’s disease that impacts on quality of life. Dyskinesias, or involuntary movements, were found to be less common than previously reported, with a mean time to onset of 6.6 years from diagnosis in this study.

At the 10 year interval, participants were grouped into two categories: “good” outcomes, where none of the 3 clinical milestones were reached (postural instability, dementia, or death), and “bad” outcomes, in which participants reached one or more of the milestones. For those who died, death certificates were obtained from the local register office.

In general, the average time to developing one of these 3 clinical milestones was 3.8 years. By 10 years, only 23% of those studied continued to be categorized as “good” outcomes and had reached none of these milestones. Those who had good outcomes tended to be younger at diagnosis, had tremor as their most prominent motor symptom, less motor dysfunction in general, better semantic fluency (the ability to produce words from memory that fit within a category, like types of animals), lower depression and fewer co-existing health conditions.

Postural instability was typically the first milestone reached in this study. Eighty-one individuals developed a significant loss of balance, resulting in a cumulative postural instability risk of 68% within 10 years of a Parkinson’s diagnosis. The average time for reaching this milestone was 4.7 years. Predictors included older age, movement symptoms dominated by stiffness and slowness rather than tremor, and a greater number of co-existing medical conditions.

The milestone of dementia developed in 41 individuals of the 142 studied. After adjusting for those who died or withdrew from the study, the figures indicate a 46% cumulative risk of developing dementia over 10 years. Those in this study were 2.6 times more likely to be diagnosed with dementia than the general population of Cambridge at a similar age. Predictors of Parkinson’s disease dementia in this study included semantic fluency, impaired visuospatial skills and greater motor dysfunction. One genetic variation (MAPT H1/H1 – a common variation in the tau gene) increased the risk of dementia in this study.

A total of 63 individuals died over the 10 years. The survival probability at 10 years was 45% and the average time to death was 10.3 years. Mortality risks were higher for those of an older age or who were smokers. Interestingly, the mortality rate amongst this PD group was not significantly higher than amongst the population as a whole at the same age. An analysis of death certificates indicated pneumonia as the most common (33%) cause of death, followed by cancer (19%) and cardiac problems (16%). Parkinson’s disease was listed as cause of death in 10%, and as a significant contributor in a further 10%. In total, 80% of death certificates did not list Parkinson’s disease as a significant contributing factor to death. Interestingly, 40% did not list Parkinson’s disease at all, which may suggest under-reporting of PD as a contributing cause of death. However, the study did not find any evidence that PD increases risk of death.

This study highlights varying rates of progression in PD. One in four may experience a relatively benign progression and be free of both postural instability and dementia at 10 years. Those individuals tend to be younger, not depressed, in better physical health, and have fewer motor symptoms. However, two thirds of older adults with PD develop postural instability within 10 years after their diagnosis, and around half develop dementia by 10 years. This study provides important insights into the variability of motor and cognitive symptom progression in Parkinson’s and underscores the importance of advance planning for personal care needs.

This paper was first published in the Journal of Neurology, Neuropsychology and Psychiatry in November, 2013. Funding was provided by the Medical Research Council, Parkinson’s UK and the National Institute of Health Research.