key: cord-0318320-d5t9wux6
authors: Huynh, K.; Nategh, L.; Jamadar, S.; Georgiou-Karistianis, N.; Lampit, A.
title: Cognition-oriented treatments and physical exercise on cognitive function in Huntington's disease: Protocol for systematic review
date: 2021-08-13
journal: nan
DOI: 10.1101/2021.08.12.21261956
sha: 1a578c581fc41e6ec1e577eb9424370eb5712001
doc_id: 318320
cord_uid: d5t9wux6

Introduction: Cognitive impairments are prevalent in Huntington's disease (HD), occurring many years prior to clinical diagnosis and are the most impactful on quality of life of patients. Cognitive interventions and exercise have been found to be efficacious in improving cognitive function in several clinical populations (e.g., older adults with mild cognitive impairment and dementia). However, the utility of cognitive interventions has not been systematically reviewed in HD. This systematic review aims to examine the efficacy of cognitive and physical interventions on cognitive function in HD. Methods: Electronic databases (MEDLINE, EMBASE, PsycINFO, CENTRAL) were searched through till 10 May 2021 for interventional studies investigating the effect of cognition-oriented treatments and physical exercise on cognitive function in individuals with HD, compared to any control or no control. The primary outcome is change on objective measures of cognition. Additional outcomes include change in psychosocial, functional and neuroimaging measures. Variations of effects based on population and study factors will be considered. Risk of bias will be assessed using the Cochrane RoB 2 tool and ROBINS-I tool. Where appropriate, outcomes will be pooled using random-effects meta-analyses, heterogeneity will be examined using tau2 and I2 statistics, and moderators will be examined using meta-regression models. Discussion: This review will systematically evaluate the efficacy of cognitive and physical interventions on improving cognitive function in HD. The eligibility criteria and planned analyses will allow for a comprehensive assessment of certainty in the evidence that will inform future trials and clinical practice. Registration: This protocol was registered on PROSPERO (CRD42021259152).

study factors will be considered. Risk of bias will be assessed using the Cochrane RoB 31 2 tool and ROBINS-I tool. Where appropriate, outcomes will be pooled using random-32 effects meta-analyses, heterogeneity will be examined using tau 2 and I 2 statistics, and 33 moderators will be examined using meta-regression models. 34

Discussion: This review will systematically evaluate the efficacy of cognitive and 35 physical interventions on improving cognitive function in HD. The eligibility criteria 36 and planned analyses will allow for a comprehensive assessment of certainty in the 37 evidence that will inform future trials and clinical practice. 38

Registration: This protocol was registered on PROSPERO (CRD42021259152). 39 Keywords: systematic review; Huntington disease; cognition; cognitive intervention; 40 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 13, 2021. cognitive function in HD have been largely inconclusive. This is partly attributed to 64 reviews including only randomized controlled trials, leading to only a few studies being 65 eligible for synthesis [13, 15] . Further, the effect of cognitive interventions has been 66 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted August 13, 2021. ; https://doi.org/10.1101/2021.08.12.21261956 doi: medRxiv preprint 5 largely unexplored in HD. To our knowledge, only one systematic review of cognitive 67 interventions in HD exists [17] . However, that review focused specifically on cognitive 68 rehabilitation, was conducted almost ten years ago, and included only one study in HD. 69

Finally, the effect of multi-domain interventions has not been assessed independently 70 from single domain interventions [14] . A comprehensive review of the effect of 71 cognitive, physical, and multi-domain interventions on cognitive function in HD, 72 including randomized and non-randomized studies, is therefore warranted. 73

The primary aim of the review is to evaluate whether cognition-oriented treatments and 75 physical exercise are associated with improved cognitive outcomes in individuals with 76 HD, compared to any control or no control. The secondary aims are to evaluate the 77 effects on psychosocial, functional and neuroimaging outcomes, and explore how these Important protocol amendments will be documented in the PROSPERO registry, and 86 divergences from the protocol will be described in the final published review paper. 87

Studies fulfilling the following criteria are eligible. 89 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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Interventional studies including randomised controlled trials, quasi-experimental 91 studies, pre-post studies with single group and interventional cohort studies will be 92 considered. Case-control studies, cross-sectional studies and case studies will be 93 excluded. 94

Participants 95

Studies including participants aged 18 or above, with clinically diagnosed manifest or 96 pre-manifest HD are eligible. Studies that include other subgroups of participants are 97 also eligible, but the review will only consider the subgroup with HD. Studies with 98 participants aged below 18 will be excluded. 99

Interventions 100 Studies assessing physical exercise or cognition-oriented treatment, either alone, 101 combined with each other, or with other non-pharmacological interventions, will be 102 considered. The intervention must include a minimum of 3 hours of physical exercise or 103 cognition-oriented treatment, either independently or combined with each other. 104

Additionally, for interventions combining physical or cognitive interventions with other 105 non-pharmacological interventions, the physical exercise and cognitive intervention 106 components must constitute at least 50% of the total intervention. Physical exercise is 107 defined as a structured activity that can improve endurance, strength, balance, or any 108 combination of these aspects. This includes walking, cycling, resistance training, 109 balance training, and mind-body exercises. Cognition-oriented treatments are defined as 110 enhancing, restorative or compensatory interventions that aim to improve cognitive 111 performance or reduce specific impairments. This includes cognitive stimulation, 112 cognitive training, and cognitive rehabilitation [7] . Social prescribing interventions that 113 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 13, 2021. ; https://doi.org/10.1101/2021.08.12.21261956 doi: medRxiv preprint 7 do not provide an intervention will be excluded. 114

Comparators 115

Studies with any type of control group, including standard care, waitlist, no contact, or 116 active control groups are eligible. Studies without control groups are also eligible. 117

Control groups comprised of people without HD will be excluded. 118

Outcomes 119

Studies are eligible if they report change in objective measures of cognition (global or 120 domain-specific) from baseline to post-intervention. Additional outcomes of interest 121 include change in measures of psychosocial well-being (e.g., mood and quality of life), 122 daily function (e.g., functional independence), and neuroimaging outcomes (e.g., brain 123 volumes). 124

No limits will be placed on year of publication, language, or country of publication. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 13, 2021. ; https://doi.org/10.1101/2021.08.12.21261956 doi: medRxiv preprint 8 outcome data, contact with authors will be attempted. 136

The search strategy for MEDLINE is presented in . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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Screening based on title and abstracts, and full-text screening against eligibility criteria 145 will be conducted independently by two reviewers. Disagreements at each stage will be 146 resolved by consensus or a third reviewer. 147

Data will be extracted to an Excel spreadsheet in duplicate by two reviewers. 149 Disagreements will be resolved by consensus or resolved by a third reviewer. If data is 150 missing or unclear, authors will be contacted to obtain data. 151

Outcomes 153

The primary outcome is change in an objective measure of cognition (either global or 154 domain-specific). Secondary outcomes include change in measures of psychosocial 155 well-being (e.g., mood, depression, anxiety, quality of life), daily function (e.g., 156 functional independence), and neuroimaging outcomes (e.g., total brain volume, caudate 157 and putamen volumes, network connectivity). 158

Outcomes will be extracted for both experimental and control groups (if 159 applicable). If multiple measures of an outcome are reported (e.g., multiple measures of 160 working memory capacity), all eligible data will be extracted. If data is reported for 161 multiple time points, we will extract data from pre-intervention to first post-intervention 162 timepoints. If results from multiple analyses are available, data from intention-to-treat 163 analyses will be preferred. 164

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The following information will also be extracted: 166

• Study information: Author, year of publication, study setting, study design 167 If information is missing or unclear following attempts to contact authors, the 176 study will be left out of relevant analyses (e.g., examining effects of specific study 177 population or intervention characteristics). 178

Risk of bias will be assessed separately for each relevant outcome in each study using 180 the Cochrane RoB 2 tool for randomised controlled trials [20] and ROBINS-I tool for 181 non-randomised studies [21] . 182

The RoB 2 tool considers: 183

(1) Bias arising from the randomisation process 184

(2) Bias due to deviations from intended interventions 185

(3) Bias due to missing outcome data 186 (4) Bias in measurement of the outcome 187 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 13, 2021. ; https://doi.org/10.1101/2021.08.12.21261956 doi: medRxiv preprint Risk of bias assessments will be conducted independently by two reviewers. 199

Disagreements between the reviewers will be resolved by discussion, with involvement 200 of a third review author where necessary. Study authors will be contacted if reports do 201 not provide sufficient details to determine risk of bias. 202

Risk of bias information will be used when considering heterogeneity (if 203 applicable) between study results, and in determining confidence in the body of 204 evidence for each outcome. 205

For each outcome, continuous data will be extracted as means and standard deviation. 207 Dichotomous (events) data will be extracted as number of individuals who did and did 208 not experience event in each group. If data is not in the desired format, data in other 209 formats (e.g., effect sizes and confidence intervals) will be extracted and converted prior 210 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 13, 2021. ; https://doi.org/10.1101/2021.08.12.21261956 doi: medRxiv preprint to synthesis of results. 211

Studies will be grouped based on study design (randomised controlled trials separated 213 from non-randomised studies), type of intervention and outcome. Studies with the same 214 design, intervention and outcome will be synthesised together. 215

For continuous data, effects will be reported as standardised mean difference 216 with 95% CI due to expected variability in the measures used across studies. For 217 dichotomous data, effects will be reported as odds ratios or risk ratios. 218

Characteristics of all included studies will be presented in a summary table. 219

Findings from syntheses will be reported in text, structured based on priority of 220 outcomes (cognitive outcomes followed by additional outcomes), followed by type of 221 intervention, and then study design (randomised controlled trials followed by non-222 randomised studies). Study results from each synthesis will be presented in summary 223 tables, and forest plots will be included where meta-analysis is conducted. 224

Where at least 3 studies are available in a group (with the same design, type of 225 intervention and outcome), results will be pooled using a multivariate random-effects 226 meta-analysis to account for non-independence of effect sizes within studies [22, 23] . 227

Analyses will be conducted using the packages metafor, metaSEM, robumeta and 228 clubSandwich for R. 229

Heterogeneity will be assessed using both the tau 2 and the I 2 statistics. If there is 230 significant heterogeneity, we will use meta-regressions to explore heterogeneity in 231 effect estimates according to risk of bias, study population and intervention 232 characteristics [24] . 233 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 13, 2021. ; https://doi.org/10.1101/2021.08.12.21261956 doi: medRxiv preprint 13 Sensitivity analyses will be performed by removing studies at higher risk of bias 234 and recalculating the pooled estimate, and additionally by comparing results from 235 multilevel and robust variance estimation models. 236

If meta-analysis is not possible, findings will be synthesised narratively and 237 similarly structured based on study design, type of intervention and outcome. Synthesis 238 will similarly consider heterogeneity and causes of heterogeneity, including risk of bias, 239 population and intervention characteristics. 240

Evidence of small-study effect will be assessed by inspecting funnel plots of effect size 242 versus standard error for each outcome [25] . Where there are at least 10 studies, we will 243 use formal statistical methods to tests for small-study effects. If summary estimates are 244 in the form of standardized mean differences, we will use Egger's test [26] . If summary 245 estimates are in the form of odds ratio, we will use the tests proposed by Peters, Sutton 246

[27] and Rücker, Schwarzer [28] when there is low between-study heterogeneity (tau 2 < 247 0.1) and substantial between-study heterogeneity (tau 2 > 0.1), respectively. Where there 248 are less than 10 studies, we will remove outliers and recalculate pooled effect sizes after 249 their removal. 250

Confidence in the body of evidence for each outcome will consider the risk of bias, 252 heterogeneity, indirectness, imprecision, and evidence of small-study effects (including 253 publication and reporting biases). 254

Cognitive impairments are prevalent in individuals with HD and greatly impact quality 256 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 13, 2021. ; https://doi.org/10.1101/2021.08.12.21261956 doi: medRxiv preprint 14 of life, but no effective pharmacological treatments are currently available [4, 5] . This 257 review will systematically evaluate the efficacy of cognition-oriented treatments and 258 physical exercise on cognitive function in HD, as there is accumulating evidence of 259 efficacy in other clinical populations. The eligibility criteria allow for the inclusion of 260 randomized and non-randomized studies, and studies that include any control or no 261 control, given the rarity of the disease and the small number of anticipated studies. The 262 planned analyses will also examine the influence of risk of bias, study population, and 263 intervention characteristics, to provide a comprehensive assessment of certainty in the 264 evidence, and to inform future trials and clinical practice. 265

No funding was acquired for this manuscript. Jamadar is supported by an Australian 267 National Health and Medical Research Council (NHMRC) Fellowship (APP1174164). 268

The authors have no conflicts of interest to declare. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

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Law C-K, Lam FMH, Chung RCK, et al. Physical exercise attenuates cognitive 308 decline and reduces behavioural problems in people with mild cognitive 309 impairment and dementia: a systematic review. J Physiother. 2020;66(1):9-18. 310 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

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