Rehabilitation of Attention in Patients With MCI and Brain Subcortical Vascular Changes Using the APT-II

Study Overview
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Brief Summary
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Background: Subcortical Vascular Dementia (VaD), consequent to deep brain small vessel disease (SVD), is the most frequent form of VaD. The term vascular mild cognitive impairment (VMCI) defines a transitional state between normal ageing and VaD. Attentional deficits are a common finding in patients affected by VMCI or subcortical VaD. At present, no drug treatment is available to prevent vascular dementia in patients with VMCI or to improve cognitive performances of this large group of patients. Cognitive rehabilitation is directed to achieve functional changes by reinforcing, strengthening, or reestablishing previously learned patterns of behavior, or establishing new patterns of cognitive activity or compensatory mechanisms. A hierarchical model of attention has been used to build the Attention Process Training-II (APT-II) programme. The APT-II programme effectiveness have been demonstrated in traumatic brain injury and post-stroke rehabilitation, but there is an increasing interest in the study of cognitive rehabilitation in pathological processes that evolve over time, such as chronic cerebrovascular diseases (CVD). Aims: The purpose of this study is to investigate whether the APT-II programme could be a useful tool in the rehabilitation of attention in individuals affected by VMCI with SVD, and if so, whether the improvement in performance is generalized to functionality in daily activities and quality of life. Main Expected Results and Impact: Considering that the APT-II contains specific exercises to facilitate generalization to daily life, the skills that are learned by each patient during the rehabilitation programme should be generalized to daily activities. Furthermore, the improvement of cognitive skills should also improve patient's overall quality of life because these learned skills are applicable to real-life situations. The main expected results are: 1) an impact of APT-II on disability, everyday cognition, quality of life, and performance on attention tests at short and long term after rehabilitation programme ending as compared with standard care; 2) a reduction of the risk of transition to dementia at 1 year follow-up as compared with control group.

Detailed Description
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Study design The present study is a 3-year prospective, single-blinded, randomized clinical trial. The enrolment will be carried out at the Stroke Unit and the VASCOG clinic of the Careggi University Hospital. Forty patients will be enrolled according to the following criteria: 1) MCI defined according to Winblad et al. criteria (19); 2) Evidence of impairment across attention neuropsychological tests; 3) Evidence on MRI of subcortical vascular lesions: moderate to severe age-related white matter changes (WMC) according to a modified version of the Fazekas scale (20). Exclusion criteria: age<18 years. All enrolled patients will be evaluated at baseline according to the study protocol, that includes: 1) Clinical assessment; 2) Functional, quality of life and mood assessment; 3) Extensive neuropsychological assessment; 4) MRI protocol. After baseline assessment, participants will be randomly assigned to attention training or standard care. Stratified minimization randomization will be used to ensure the balance for possible prognostic factors (i.e., age, gender, MMSE total score, extension and localization of WMC) across the groups. All APT-II sessions will be administered by a clinical neuropsychologist, or an appositely trained graduate student in medicine. The student clinicians will receive a minimum of 30 hours of training with adult rehabilitation patients, and will be closely supervised by the neuropsychologist. Participants in the APT-II group will receive overall up to 40 hours of individual attention process training. Therapy will be administered in one two-hour session each week over a total of 20 weeks. Participants in the standard care group will not receive cognitive training or rehabilitation interventions, will be instructed to have an usual lifestyle, and will be conventionally provided of medication and clinic consultations. Each patient will be followed-up at 6 and 12 months after baseline assessment. During the follow-up visits clinical assessment, an extensive neuropsychological evaluation, and mood, functional, and quality of life assessments will be performed according to the baseline protocol. The MRI protocol will be repeated at 1-year follow-up. Work Methodology Baseline and follow-up clinical, neuropsychological, functional, and MRI data will be collected in a dedicated database. Data will be checked and controlled for consistency in real time during collection. At the end of the enrolment, a first exploratory data analysis will be carried out. Postprocessing of neuroimaging acquired at baseline will be performed by an experienced radiologist. At the end of each follow-up (6 and 12 months after enrollment), analysis of data (uni- and multivariate models and effect size measures) will be carried out. All analyses will be performed using SPSS 18 and will be mainly directed to: 1) evaluate the short and long-term effectiveness of the rehabilitation program, using cognitive performance and functional and quality of life measures as dependents variables (within and between groups analyses); 2) identify potential predictors of effectiveness of the rehabilitation program (multivariate model). The variables included in the model will be: demographic and vascular risk factors, baseline cognitive profile and functional status, and preexisting brain structural changes; 3) evaluate the potential protective effect of the rehabilitation program on the increase of cognitive impairment or transition to dementia at 1 year follow-up; 4) evaluate the long-term effect of rehabilitation on brain activation, using f-MRI data, whole-brain histograms, and voxel-based analyses as dependents variables (within and between groups analyses). Milestones Phase 1 (4 months): 1) Project protocol establishment; 2) Dedicated database for data collection construction; 3) MRI protocol determination; 4) Training on cognitive rehabilitation Phase 2 (24 months): 1) Baseline patients cohort enrolment and clinical, neuropsychological, functional, and MRI data collection; 2) Neuropsychological rehabilitation program administration; 3) Follow-up assessments (6 and 12 months after enrolment) Phase 3 (8 months): 1) Post-processing of neuroimaging acquired at baseline and at 1-year follow-up; 2) Data completeness and consistency control; 3) Data analysis; 4) Dissemination of results

Official Title
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The Rehabilitation of Attention in Patients With Mild Cognitive Impairment and Brain Subcortical Vascular Changes Using the Attention Process Training-II

Conditions
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Mild Cognitive Impairment

Intervention / Treatment
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* Behavioral: Attention Process Training-II


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients will be enrolled according to the following criteria: MCI defined according to Winblad et al. criteria; Evidence of impairment across attention neuropsychological tests; Evidence on MRI of subcortical vascular lesions: moderate to severe age-related white matter changes (WMC) according to a modified version of the Fazekas scale. Exclusion Criteria: Age < 18 years

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: APT-II group<br>Intervention: rehabilitation of attention using the Attention Process Training-II. Participants in the APT-II group will receive overall up to 40 hours of individual attention process training. Therapy will be administered in one two-hour session each week over a total of 20 weeks. | Behavioral: Attention Process Training-II<br>* Rehabilitation of attention using the Attention Process Training-II<br>|
| No Intervention: standard care group<br>Participants in the standard care group will not receive cognitive training or rehabilitation interventions, will be instructed to have an usual lifestyle, and will be conventionally provided of medication and clinic consultations | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Functionality in Activities of Daily Living (Changes in Scores Approach) | Changes in scores (Δ) approach. Delta scores (Δs) were calculated by computing the difference between the scores obtained in 2 evaluations (baseline vs. 6 months; 6 vs. 12 months; baseline vs. 12 months) for each patient. All Δs were calculated in order that a positive score indicates an improvement, while a negative score indicates a worsening. Δs were analyzed using independent sample t tests with treatment as the only independent variable. Scales: Activities of Daily Living (ADL): preserved items summed into a global score (minimum and maximum values 0-6: higher scores mean a better outcome). Instrumental Activities of Daily Living (IADL): impaired items summed into a global score (minimum and maximum values 0-8: higher scores mean a worse outcome). Disability Assessment in Dementia (DAD): 40 dichotomous items summed into a total score and converted into a percentage (minimum and maximum values 0-100: higher scores mean a worse outcome). | Baseline, 6 months and 12 months | 
| Quality of Life (Changes in Scores Approach) | Changes in scores (Δ) approach. Delta scores (Δs) were calculated by computing the difference between the scores obtained in 2 evaluations (baseline vs. 6 months; 6 vs. 12 months; baseline vs. 12 months) for each patient. All Δs were calculated in order that a positive score indicates an improvement, while a negative score indicates a worsening. Δs were analyzed using independent sample t tests with treatment as the only independent variable. Scales: Short Form Health Survey summary scores: Physical and Mental Component Summary (PCS, MCS) (minimum and maximum values 0-100: lower scores mean worse outcome). EuroQol (EQ): summary index (min-max values 0-1) and visual analogue scale (minimum and maximum values 0-100: higher scores mean better outcome). Attention Questionnaire (AQ) total score (minimum and maximum values 0-36: higher scores mean worse outcome). Geriatric Depression Scale (GDS) total score (minimum and maximum values 0-15: higher scores mean worse outcome). | Baseline, 6 months and 12 months | 
| Quality of Life (Clinically Significance Approach) | Clinically significance approach. The availability of t scores for the Short Form Health Survey (SF-36) Physical and Mental Component Summary scores (MCS, PCS) allowed us to classify each patient evaluation as 'normal well-being' (t score >40) or 'reduced well-being' (t score ≤40) at each visit (higher scores mean a better outcome). Variations in performance categories over time (baseline vs. 6 month; 6 vs. 12 month; baseline vs. 12 month) were evaluated for each patient and dichotomized as: 'stable or better evaluation' or 'worst evaluation'. Variations in performance categories were analyzed using chi square tests. | Baseline, 6 months and 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cognitive Performance (Changes in Scores Approach) | Delta (Δ) scores were calculated by computing the difference between the scores obtained in 2 evaluations (baseline vs. 6 months; 6 vs. 12 months; baseline vs. 12 months) for each patient. A positive Δ score indicates an improvement, while a negative Δ score indicates a worsening. Delta scores were analyzed using independent sample t tests with treatment as the only independent variable. Test battery: Montreal Cognitive Assessment MoCA (minimum and maximum values 0-30); Mini Mental Status Examination MMSE (minimum and maximum values 0-30), Rey Auditory-Verbal Learning RAVL immediate (minimum and maximum values 0-75) and recall (minimum and maximum values 0-15), Short story (minimum and maximum values 0-28), Rey-Osterrieth Complex Figure ROCF copy and recall (minimum and maximum values 0-36), Visual search (minimum and maximum values 0-50), Symbol Digit Modalities Test SDMT (minimum and maximum values 0-110). Higher scores mean better outcome for all tests. | Baseline, 6 months and 12 months | 
| Cognitive Performance TMT-A, TMT-B, Stroop (Changes in Scores Approach) | Delta (Δ) scores were calculated by computing the difference between the scores obtained in 2 evaluations (baseline vs. 6 months; 6 vs. 12 months; baseline vs. 12 months) for each patient. A positive Δ score indicates an improvement, while a negative Δ score indicates a worsening. Delta scores were analyzed using independent sample t tests with treatment as the only independent variable. Cognitive tests based on execution time in seconds: Trail Making Test TMT part A (minimum and maximum values 0-300), TMT part B (minimum and maximum values 0-300), and Stroop Test (minimum and maximum values 0-300). Higher scores mean worse outcome. | Baseline, 6 months and 12 months | 
| Cognitive Performance Verbal Fluency (Changes in Scores Approach) | Delta (Δ) scores were calculated by computing the difference between the scores obtained in 2 evaluations (baseline vs. 6 months; 6 vs. 12 months; baseline vs. 12 months) for each patient. A positive Δ score indicates an improvement, while a negative Δ score indicates a worsening. Delta scores were analyzed using independent sample t tests with treatment as the only independent variable. Cognitive tests based on the total number of words produced: phonemic (minimum and maximum values not applicable) and semantic verbal fluency (minimum and maximum values not applicable). Higher scores mean better outcome for both tests. | Baseline, 6 months and 12 months | 
| Cognitive Performance (Clinically Significance Approach) | Clinically significance approach. The availability of national norms for the cognitive variables allowed us to classify each patient's performance as 'normal', 'borderline' or 'abnormal' at each visit. Variations in performance categories over time (baseline vs. 6 month; 6 vs. 12 month; baseline vs. 12 month) were evaluated for each patient and dichotomized as: 'stable or better evaluation' or 'worst evaluation'. Variations in performance categories were analyzed using chi square tests. Test battery: global cognitive functioning: Montreal Cognitive Assessment, MoCA; Mini Mental Status Examination, MMSE memory: Rey Auditory-Verbal Learning (RAVL) immediate and recall, Short story, Rey-Osterrieth Complex Figure (ROCF) recall attention/executive function: Trail Making Test part A and B (TMT-A and B), Visual search, Symbol Digit Modalities Test (SDMT), Stroop Test language: phonemic and semantic verbal fluency constructional praxis: ROCF copy | Baseline, 6 months and 12 months | 
| Transition to Dementia | Data collected during the 1-year follow-up visit were used to evaluate the occurrence of a transition from MCI to dementia according to DSM-V criteria. Chi square test for a 2x2 contingency table was used to compare patients who became demented at 1-year follow-up visit with those who did not, in the two treatment groups. | 12 months | 
| Cognitive Plasticity | Improvement in long-term brain activity was measured by means of regional homogeneity (ReHo) of resting state functional MRI (rsfMRI) data. Statistical analysis of rsfMRI data was carried out by feeding Z-transformed ReHo data into voxel-wise inter-subject statistics using permutation-based nonparametric inference within the general linear model framework. P-values were calculated employing permutation-based statistics and corrected for multiple comparisons using the 3D parameter settings with threshold-free cluster enhancement, and a p-value <0.05 was considered statistically significant. Z-transformed ReHo differences (12 months-baseline) were computed separately for treated and non-treated patients, and a voxel-wise between-group comparison was used to evaluate the treatment effect . A positive mean of the Z-transformed ReHo differences represents an increase in activation over time (better outcome), and a negative mean represents a decrease in activation over time (worse outcome). | Baseline, 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cognition, small vessel disease, treatment, rehabilitation, attention, fMRI, vascular dementia