The New Zealand Parkinson's progression programme

Abstract

We describe the New Zealand Parkinson's Progression Programme (NZP3), its goals, findings, and future plans. To date, 354 people with Parkinson's disease and 89 healthy older controls have participated over a 14-year period. A major focus of the programme has been the characterisation of current cognitive impairment, and the identification of biomarkers for its future emergence in people with Parkinson's. The programme has made significant contributions to the concept of mild cognitive impairment (MCI) in Parkinson's and the development and validation of standardised criteria for it. Brain imaging, both MRI and PET, has also been a focus, showing associations between increasing brain pathology and declining cognitive function. Additional biomarkers such as genetics, fluid biomarkers, eye movement, speech, and quantitative electroencephalography (EEG) are also under investigation. The programme has become a platform supporting many other avenues of research, from investigating the personal impacts of caregiver burden through to national-level epidemiology. To date, the programme has led to multiple journal publications and 17 completed and 9 ongoing PhDs, and many other postgraduate theses. It has led to the development of a skilled core of early-career through to senior researchers and clinicians. We discuss the future directions for the programme.

Keywords: Parkinson’s disease; cognitive impairment; dementia; longitudinal assessment; neuropsychology.

Figure 1.

Examples of data collected in the programme from Parkinson’s participants with normal cognition (PDN), mild cognitive impairment (PD-MCI), and dementia (PDD). The top row shows group-level progression across groups in the extent of cortical thinning relative to controls. The consequences of this are shown in this selection of neuropsychological tests from three representative male participants (PDN: age 68, 8 years symptom duration; PD-MCI: age 72, 6 years duration; PDD: age 60, 5 years duration; all with 10–11 years of education). The PDN participant shows good performance in the trail-making test of executive function, and the visuo-spatial tests of drawing a clock and copying a complex figure. The memory ability that allows drawing that figure again after delays of 3 and 30 min is also relatively preserved. The PD-MCI participant shows good trail making and only mildly disorganised clock drawing and figure copying. The ability to redraw the complex figure from memory, however, is somewhat degraded. The participant with dementia is severely impaired on all of the tasks. Figure available under an open CC-BY licence (MacAskill and Horne 2021).

Figure 2.

A, Individual assessment timelines through the duration of the study, with most participants assessed multiple times. B, Recruitment of new participants has occurred in a pulsatile fashion, depending on commencement of discrete major sub-studies. C, Assessments have been continuous, however, as efforts are made to continually track existing participants (with recent interruptions due to COVID-19). D, Survival curves showing the study duration of Parkinson’s participants: ongoing recruitment is required to balance drop-outs due to mortality and other factors. Figure available under an open CC-BY licence (MacAskill 2022).

Figure 3.

Here we depict the core dataset of the study: individual trajectories of cognitive status from all participants. Each point represents a summary measure of one participant’s comprehensive neuropsychological assessment (the mean z-score of the component tests grouped within each of five cognitive domains). Dementia is the end-point for gathering this measure, as administering the full test battery becomes infeasible beyond that point. The diagnostic categories are represented by green circles (normal functioning), yellow triangles (mild cognitive impairment), or red squares (dementia). Controls show a pattern of relatively stable cognitive functioning over a wide age range, with only a few showing mild cognitive impairment, and one declining to dementia to date. While the younger Parkinson’s participants also show relatively stable functioning, a large proportion eventually develop mild cognitive impairment and many progress to dementia. A proportion, however, retains good functioning even into very old age. Understanding this heterogeneity in the course of disease is the main goal of the research programme. Figure available under an open CC-BY licence (MacAskill 2021a).

Figure 4.

Depiction of a sub-study in which we used positron emission tomography (PET) imaging to measure cerebral amyloid in Parkinson’s (Melzer et al. 2019). This illustrates the complexity of longitudinal research in patients who can change (not always unidirectionally) between diagnostic categories, who do not always attend all scheduled sessions, and who are also at substantial risk of dropping out due to mortality and morbidity. We began with a sub-sample enriched to over-represent PD-MCI (74 participants at baseline, shown in orange), with smaller reference groups of PDN (green, n = 26) and PDD (red, n = 18). Coloured boxes show the number of participants within each category at (ideally) 6-monthly assessment intervals over a three year period. Grey boxes indicate those who were lost to follow-up at each assessment, due to death or other factors. Numbers in a lighter-weight font indicate transitions between different categories. Only one person appeared to transition directly (between assessments at 18 and 30 months) from PDN to PDD: otherwise, all conversions to dementia were detected via the intermediate stage of PD-MCI. Some PD-MCI participants, meanwhile, reverted to being classified as PDN, indicating the inherent difficulty in determining the boundary between the two states. Although the number of people with PDD appears to have been relatively constant throughout the study, only one person who entered the study with PDD actually survived to completion: the remainder developed dementia during the study. Figure available under an open CC-BY licence (MacAskill 2021b).

Figure 5.

Longitudinal measurement of grey matter volume in the NZP3 study. The control participants show a typical age-related linear decline of 0.22 percentage points per year. The Parkinson’s participants declined at a slightly but statistically significantly faster rate (by an additional 0.06% per year). Figure available under an open CC-BY licence (MacAskill and Melzer 2021).

Figure 6.

A new direction for motor control research in the programme is applying advanced deep-learning pose estimation techniques (Nath et al. 2019) from video recordings in non-laboratory settings. Here the algorithm automatically identifies and tracks hand joints in a repetitive finger-tapping task. The extracted quantitative data shows progressive bradykinesia, i.e. fatiguing (decreasing movement amplitude over time) and an increased interval between successive movements. Figure available under an open CC-BY licence (Marshall and MacAskill 2022).