Clinical trial NCT03680170: Cognitive Training in Parkinson's Disease, the iPARK Study
Official title: The Effect of Home-based Working Memory Updating Training on Cognition and Health in Patients With Parkinson's Disease
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Parkinson Disease
Cognitive Impairment
Keywords: Cognitive rehabilitation
Working memory
Randomized controlled trial
Placebo control
Lead sponsor: Umeå University
Sponsor class: OTHER
Collaborators: name: Karlstad University
First posted: 2018-09-21
Enrollment: 80
Sex: ALL
Minimum age (years): 45
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Two parallel assigned intervention groups with randomized allocation.The intervention of focus is a web-based working memory updating training. The placebo condition consists of a web-based low dose short term memory training. Both groups received pretesting (pre-test) before 30 sessions (6-8 weeks) of training followed by immediate post-testing (post-test 1) and a long term follow up four months after training (post-test 2)
Primary purpose: TREATMENT

Brief summary: The aim of the iPARK-study is to investigate the effects of a process-based cognitive training program with focus on working memory in patients with Parkinson's Disease (PD). The study is a double blinded, randomized controlled trial with a parallel group design that aim to recruit 80 persons with PD. All patients will undergo 30 sessions (6-7 weeks) of web-based cognitive training performed at home. The working memory training is a process-based training program focusing specific on updating. The placebo program is a low dose short term memory paradigm without updating. A battery of neuropsychological tests (working memory, attention, episodic memory, inhibition control, risk taking and motoric speed) and questionnaires (everyday functioning and psychological health) will be performed before training and directly after training and after 16 weeks. Patient expectation and measures of adherence (motivation and results during training) will be controlled for.

The iPARK trial is expected to provide novel and clinical useful information whether updating training is an effective training paradigm in PD. Further it will hopefully contribute to a better understanding of cognitive function in PD.

Detailed description: Parkinson's Disease (PD) is after Alzheimers disease (AD) the most common neurodegenerative disease with a prevalence of 1% of the population over 60 years of age. The cardinal symptoms are motoric and are believed to be caused by depletion of dopamine in the brain with severe depletion in the striatum. In addition to the motor impairments, there are several non-motor functions also affected, where cognitive decline and dementia are among the most common problems. Some claim that up to 75% of the total PD population will eventually develop dementia. Prior to dementia, milder cognitive problems are common and already at the time of diagnosis up to 42.5% of patients with PD are affected by decline in different cognitive functions. Early cognitive deficits seen is inhibition, shifting, working memory and planning, but a cognitive profile of visuospatial decline, semantic fluency and episodic memory has been connected to Parkinson's Disease Dementia (PDD). The occurrence of Lewy-bodies and Alzheimer type brain pathology is common in PDD but dopamine depletion has also been connected to cognitive decline in healthy elderly and in PD.

Although prescription of dementia medication in PD most likely has increased during the last decade there are limited evidence of treatment effects . This particular patient group is already burdened by polypharmacy and therefore investigating non-pharmacological interventions is of crucial importance. A recent systematic review of cognitive intervention studies in PD suggests that there is evidence of clinically meaningful improvements in overall cognition and moderate to large effect sizes on measures of working memory, processing speed and executive functions. Another review on the topic suggested that the results are promising, at least in the immediate or short term for some cognitive domains, but due to inconsistencies between studies and lack of methodological salience there are still a lot of questions unanswered. Baseline factors such as cognitive functioning, Hoehn and Yahr stage, premorbid intelligence all can have contributing effects on individual differences in training gain. Therefore it is important to thoroughly investigate baseline characteristics.

In the future, studies need to include more participants, be hypothesis driven and include more detail of the cognitive profile, training intervention and outcome measures.

One approach to cognitive training that has received a lot of attention and critique is process-based cognitive training, such as training focusing on working memory (WM) and executive functions (EF). The purpose of the process based approach is to strengthen general cognitive processes important to global cognitive functioning. WM and EF play central roles in several different functions such as episodic memory, reading comprehension and problem solving to mention a few. Research has also shown that WM and EF is negatively affected both in normal and pathological aging, such as PD.

Training of executive functioning and working memory have gained some promising results in healthy adults, showing improvements in working memory and executive functioning but there is also an indication of broader generalizations of training gain. Previously the effect of process-based updating training in healthy young and older individuals has been studied. Results showed that a period of updating training increased Blood Oxygen Level Dependent (BOLD) activity in striatum related to increased cognitive performance in both groups. Also a corresponding effect of training on dopaminergic neurotransmission was detected.

In the light of the dopamine dysfunction in PD, with negative effects on both motoric and cognitive function it is of interest to study if a non-invasive, non-pharmacological intervention can lead to better updating function with increased dopamine levels in patients with PD. The iPARK study is a double blinded randomized controlled trial that will examine the effect of a web-based cognitive training program with focus on updating training.

The primary question asked will be if updating training will improve the ability to update contents in working memory and also if there will be improvements in other cognitive functions such as psychomotor speed, working memory, executive functions and episodic memory. Further the aim is to investigate if there will be improvements in self-perceived everyday cognitive function and psychological health as well as if the effects seen will be sustained over a period of four months. Baseline factors will be investigated to see if they have a modulating effect on training. Further the iPARK trial will determine if a web-based training performed at home without active supervision is a feasible approach in this particular patient group. Compliance, adherence and expectations will be measured systematically.

Eligibility criteria: Inclusion Criteria:

1. Diagnosis of Parkinson's Disease according to United Kingdom Parkinson's Disease Brain Bank (UKPDSBB) criteria
2. Hoehn and Yahr stage I-III
3. Pathological dat scan
4. A score of 24 or over on the MMSE AND be without Dementia
5. Stable medication over the past three months
6. Owns and is able to use a home based computer or tablet with internet connection.

Exclusion Criteria:

1. Unstable medication
2. Ongoing cognitive training
3. Diagnosis of PDD
4. Drug or alcohol abuse

Primary outcomes:
measure: Criterion task
timeFrame: 6-8 weeks (pretest-posttest 1)
measure: Criterion task
timeFrame: 16 weeks (posttest 1-posttest 2)
Secondary outcomes:
measure: Transfer task n-back
timeFrame: 6-8 weeks (pretest-posttest 1)
measure: Transfer task n-back
timeFrame: 16 weeks (posttest 1-posttest 2)
measure: Transfer task digit memory running span
timeFrame: 6-8 weeks (pretest-posttest 1)
measure: Transfer task digit memory running span
timeFrame: 16 weeks (posttest 1-posttest 2)
measure: Updating total score
timeFrame: 6-8 weeks (pretest-posttest 1)
measure: Updating total score
timeFrame: 16 weeks (posttest 1-posttest 2)
measure: Transfer task episodic memory
timeFrame: 6-8 weeks (pretest-posttest 1)
measure: Transfer task episodic memory
timeFrame: 16 weeks (posttest 1-posttest 2)
measure: Transfer task digit span
timeFrame: 6-8 weeks (pretest-posttest 1)
measure: Transfer task digit span
timeFrame: 16 weeks (posttest 1-posttest 2)
measure: Transfer task visuospatial-span
timeFrame: 6-8 weeks (pretest-posttest 1)
measure: Transfer task visuospatial-span
timeFrame: 16 weeks (posttest 1-posttest 2)
measure: working memory total score
timeFrame: 6-8 weeks (pretest-posttest 1)
measure: working memory total score
timeFrame: 16 weeks (posttest 1-posttest 2)
measure: Transfer task Matrices (WAIS IV)
timeFrame: 6-8 weeks (pretest-posttest 1)
measure: Transfer task Matrices (WAIS IV)
timeFrame: 16 weeks (posttest 1-posttest 2)
measure: Transfer task Digit symbol
timeFrame: 6-8 weeks (pretest-posttest 1)
measure: Transfer task Digit symbol
timeFrame: 16 weeks (posttest 1-posttest 2)
measure: Transfer task Perdue pegboard
timeFrame: 6-8 weeks (pretest-posttest 1)
measure: Transfer task Perdue pegboard
timeFrame: 16 weeks (posttest 1-posttest 2)
measure: Mental and psychomotor speed total score
timeFrame: 6-8 weeks (pretest-posttest 1)
measure: Mental and psychomotor speed total score
timeFrame: 16 weeks (posttest 1-posttest 2)
measure: Transfer task Stroop test
timeFrame: 6-8 weeks (pretest-posttest 1)
measure: Transfer task Stroop test
timeFrame: 16 weeks (posttest 1-posttest 2)
measure: Transfer task Trail Making Test
timeFrame: 6-8 weeks (pretest-posttest 1)
measure: Transfer task Trail Making Test
timeFrame: 16 weeks (posttest 1-posttest 2)
measure: Executive function total score
timeFrame: 6-8 weeks (pretest-posttest 1)
measure: Executive function total score
timeFrame: 16 weeks (posttest 1-posttest 2)
measure: Transfer task subjective cognitive complaints
timeFrame: 6-8 weeks (pretest-posttest 1)
measure: Transfer task subjective cognitive complaints
timeFrame: 16 weeks (posttest 1-posttest 2)
Other outcomes:
measure: Hospital Anxiety Depression scale (Depression and anxiety)
timeFrame: 6-8 weeks (pretest- posttest 1) 16 weeks (posttest 1 - posttest 2)
measure: Short Form Health Survey sf-36 (Health status)
timeFrame: 6-8 weeks (pretest- posttest 1) 16 weeks (posttest 1 - posttest 2)
measure: Short version of the Karolinska Sleep Questionnaire (Sleep status)
timeFrame: 6-8 weeks (pretest- posttest 1) 16 weeks (posttest 1 - posttest 2)
measure: Parkinson's Disease Questionnaire PDQ-39 (Function and well being)
timeFrame: 6-8 weeks (pretest- posttest 1) 16 weeks (posttest 1 - posttest 2)
measure: Urgency, Premeditation, Perseverance and Sensation Seeking Questionnaire UPPS (Impulsivity and risk taking)
timeFrame: 6-8 weeks (pretest- posttest 1) 16 weeks (posttest 1 - posttest 2)
measure: Balloon Analogue Risk Taking Task BART (Impulsivity and risk taking)
timeFrame: 6-8 weeks (pretest- posttest 1) 16 weeks (posttest 1 - posttest 2)
measure: Checklist Individual Strength Questionnaire CIS (Fatigue)
timeFrame: 6-8 weeks (pretest- posttest 1) 16 weeks (posttest 1 - posttest 2)
measure: Adherence (Task engagement)
timeFrame: 6-8 weeks (during training)
measure: Compliance (Finishing training within time frame)
timeFrame: 6-8 weeks (during training)
measure: Age
timeFrame: before training (pretest)
measure: sex
timeFrame: before training (pretest)
measure: Educational level
timeFrame: before training (pretest)
measure: Disease duration
timeFrame: before training (pretest)
measure: Disease stage
timeFrame: before training (pretest)
measure: Levodopa Equivalent Dose (Medication for Parkinson's Disease)
timeFrame: 6-8 weeks (pretest- posttest 1) 16 weeks (posttest 1 - posttest 2)
measure: Unified Parkinson's Disease Rating Scale (Motor symptoms)
timeFrame: before training (pretest)
measure: Mini Mental State Examination (Global cognitive function)
timeFrame: before training (pretest)
measure: Side (left or right) most affected of Parkinson's Disease symptoms
timeFrame: before training (pretest)
measure: Swedish vocabulary test SRB (Verbal ability)
timeFrame: before training (pretest)
measure: Incidence of Treatment-Emergent Adverse Events (Safety and tolerability)
timeFrame: 6-8 weeks (during training and at post test)
Locations:
city: Umea
country: Sweden
facility: Umeå University department of psychology
state: Västerbotten
Study officials:
affiliation: Karlstad University
name: Anna S Neely, Prof
role: PRINCIPAL_INVESTIGATOR
References:
citation: de Lau LM, Breteler MM. Epidemiology of Parkinson's disease. Lancet Neurol. 2006 Jun;5(6):525-35. doi: 10.1016/S1474-4422(06)70471-9.
citation: Aarsland D, Kurz MW. The epidemiology of dementia associated with Parkinson disease. J Neurol Sci. 2010 Feb 15;289(1-2):18-22. doi: 10.1016/j.jns.2009.08.034. Epub 2009 Sep 4.
citation: Elgh E, Domellof M, Linder J, Edstrom M, Stenlund H, Forsgren L. Cognitive function in early Parkinson's disease: a population-based study. Eur J Neurol. 2009 Dec;16(12):1278-84. doi: 10.1111/j.1468-1331.2009.02707.x. Epub 2009 Jun 15.
citation: Yarnall AJ, Breen DP, Duncan GW, Khoo TK, Coleman SY, Firbank MJ, Nombela C, Winder-Rhodes S, Evans JR, Rowe JB, Mollenhauer B, Kruse N, Hudson G, Chinnery PF, O'Brien JT, Robbins TW, Wesnes K, Brooks DJ, Barker RA, Burn DJ; ICICLE-PD Study Group. Characterizing mild cognitive impairment in incident Parkinson disease: the ICICLE-PD study. Neurology. 2014 Jan 28;82(4):308-16. doi: 10.1212/WNL.0000000000000066. Epub 2013 Dec 20.
citation: Kehagia AA, Barker RA, Robbins TW. Neuropsychological and clinical heterogeneity of cognitive impairment and dementia in patients with Parkinson's disease. Lancet Neurol. 2010 Dec;9(12):1200-1213. doi: 10.1016/S1474-4422(10)70212-X. Epub 2010 Sep 27.
citation: Landau SM, Lal R, O'Neil JP, Baker S, Jagust WJ. Striatal dopamine and working memory. Cereb Cortex. 2009 Feb;19(2):445-54. doi: 10.1093/cercor/bhn095. Epub 2008 Jun 11.
citation: Ekman U, Eriksson J, Forsgren L, Mo SJ, Riklund K, Nyberg L. Functional brain activity and presynaptic dopamine uptake in patients with Parkinson's disease and mild cognitive impairment: a cross-sectional study. Lancet Neurol. 2012 Aug;11(8):679-87. doi: 10.1016/S1474-4422(12)70138-2. Epub 2012 Jun 27.
citation: Ito K, Nagano-Saito A, Kato T, Arahata Y, Nakamura A, Kawasumi Y, Hatano K, Abe Y, Yamada T, Kachi T, Brooks DJ. Striatal and extrastriatal dysfunction in Parkinson's disease with dementia: a 6-[18F]fluoro-L-dopa PET study. Brain. 2002 Jun;125(Pt 6):1358-65. doi: 10.1093/brain/awf134.
citation: Seppi K, Weintraub D, Coelho M, Perez-Lloret S, Fox SH, Katzenschlager R, Hametner EM, Poewe W, Rascol O, Goetz CG, Sampaio C. The Movement Disorder Society Evidence-Based Medicine Review Update: Treatments for the non-motor symptoms of Parkinson's disease. Mov Disord. 2011 Oct;26 Suppl 3(0 3):S42-80. doi: 10.1002/mds.23884.
citation: Leung IH, Walton CC, Hallock H, Lewis SJ, Valenzuela M, Lampit A. Cognitive training in Parkinson disease: A systematic review and meta-analysis. Neurology. 2015 Nov 24;85(21):1843-51. doi: 10.1212/WNL.0000000000002145. Epub 2015 Oct 30.
citation: Glizer D, MacDonald PA. Cognitive Training in Parkinson's Disease: A Review of Studies from 2000 to 2014. Parkinsons Dis. 2016;2016:9291713. doi: 10.1155/2016/9291713. Epub 2016 Sep 5.
citation: Klingberg T. Training and plasticity of working memory. Trends Cogn Sci. 2010 Jul;14(7):317-24. doi: 10.1016/j.tics.2010.05.002. Epub 2010 Jun 16.
citation: Morrison AB, Chein JM. Does working memory training work? The promise and challenges of enhancing cognition by training working memory. Psychon Bull Rev. 2011 Feb;18(1):46-60. doi: 10.3758/s13423-010-0034-0.
citation: Shipstead Z, Redick TS, Engle RW. Is working memory training effective? Psychol Bull. 2012 Jul;138(4):628-654. doi: 10.1037/a0027473. Epub 2012 Mar 12.
citation: Unsworth N, Engle RW. Simple and complex memory spans and their relation to fluid abilities: Evidence from list-length effects. Journal of Memory and Language 54(1): 68-80, 2006.
citation: Unsworth N, Engle RW. The nature of individual differences in working memory capacity: active maintenance in primary memory and controlled search from secondary memory. Psychol Rev. 2007 Jan;114(1):104-32. doi: 10.1037/0033-295X.114.1.104.
citation: Gabrieli JDE, Singh J, Stebbins GT, & Goetz CG. Reduced working memory span in Parkinson's disease: Evidence for the role of frontostriatal system in working and strategic memory. Neuropsychology, 10(3): 322-332,1996.
citation: McCabe DP, Roediger HL, McDaniel MA, Balota DA, Hambrick DZ. The relationship between working memory capacity and executive functioning: evidence for a common executive attention construct. Neuropsychology. 2010 Mar;24(2):222-243. doi: 10.1037/a0017619.
citation: Chein JM, Morrison AB. Expanding the mind's workspace: training and transfer effects with a complex working memory span task. Psychon Bull Rev. 2010 Apr;17(2):193-9. doi: 10.3758/PBR.17.2.193.
citation: Dahlin E, Neely AS, Larsson A, Backman L, Nyberg L. Transfer of learning after updating training mediated by the striatum. Science. 2008 Jun 13;320(5882):1510-2. doi: 10.1126/science.1155466.
citation: Backman L, Nyberg L, Soveri A, Johansson J, Andersson M, Dahlin E, Neely AS, Virta J, Laine M, Rinne JO. Effects of working-memory training on striatal dopamine release. Science. 2011 Aug 5;333(6043):718. doi: 10.1126/science.1204978.
citation: Dahlin E, Nyberg L, Backman L, Neely AS. Plasticity of executive functioning in young and older adults: immediate training gains, transfer, and long-term maintenance. Psychol Aging. 2008 Dec;23(4):720-30. doi: 10.1037/a0014296.
citation: Backman L, Waris O, Johansson J, Andersson M, Rinne JO, Alakurtti K, Soveri A, Laine M, Nyberg L. Increased dopamine release after working-memory updating training: Neurochemical correlates of transfer. Sci Rep. 2017 Aug 2;7(1):7160. doi: 10.1038/s41598-017-07577-y.
citation: Domellof ME, Walton L, Boraxbekk CJ, Backstrom D, Josefsson M, Forsgren L, Stigsdotter Neely A. Evaluating a frontostriatal working-memory updating-training paradigm in Parkinson's disease: the iPARK trial, a double-blinded randomized controlled trial. BMC Neurol. 2020 Sep 7;20(1):337. doi: 10.1186/s12883-020-01893-z.